CN102414207A

CN102414207A - Fluorinated aminotriazole derivatives

Info

Publication number: CN102414207A
Application number: CN2010800182936A
Authority: CN
Inventors: 丹尼尔·布尔; 奥利维尔·考米波夫; 塞尔文·库恩; 科琳娜·格里索斯托米; 泽维尔·莱罗尔; 西尔维娅·里卡德-比尔德斯滕
Original assignee: Actelion Pharmaceuticals Ltd
Current assignee: Aidu West Pharmaceutical Co. Ltd.
Priority date: 2009-06-09
Filing date: 2010-06-07
Publication date: 2012-04-11
Anticipated expiration: 2030-06-07
Also published as: KR101444559B1; ZA201200127B; CA2760588A1; MX342440B; MX2011012739A; BRPI1010738A8; CN102414207B; TWI404717B; EP2440555B1; CL2011003097A1; IL216792A; US20120101138A1; MY161243A; TW201102383A; JP2012529491A; WO2010143116A1; PL2440555T3; AU2010258334A1; CA2760588C; JP5775496B2

Abstract

The invention relates to fluorinated aminotriazole derivatives of formula (I), wherein A, R1 and R2 are as defined in the description, their preparation and their use as pharmaceutically active compounds.

Description

Fluoridize aminotriazole derivatives

Technical field

The present invention fluoridizes aminotriazole derivatives about formula (I), and as medical purposes.The present invention comprises the method for preparing this compound also about some related fields, contains the medical composition of one or more formula (I) compound, and especially it urges the purposes of agent as the ALX acceptor.

Background technology

ALXR (another name lipoxin A 4 acceptors, FPRL1, FPR2; Be disclosed as nucleotide sequence SEQ ID NO:1 and aminoacid sequence SEQ ID NO:2 at WO2003/082314) be a member of G-protein coupled receptor group.Found that ALXR can mediate calcium and move, with the formyl radical-methionine(Met)-leucyl-phenylalanine(Phe) polypeptide of response high density.Moreover, found the lipid metabolism product, lipoxin A 4 (LXA4), and analogue; Can combine ALXR with high-affinity, and increase arachidonic acid production and the effect of G-protein activation in the ALXR transfectional cell (people such as Chiang, Pharmacol.Rev.; 2006,58, the 463-487 page or leaf).The effect of LXA4 in multiple Animal diseases pattern by being assessed, and LXA4 is proved and has the effective anti-inflammatory and the activity that disappears in advance.Disease pattern; Wherein LXA4 or verivate or stable analogue can represent activity in vivo vivid; Be proliferative glomerulonephritis between for example corium inflammation, dorsal part air bag, exhausted blood/reperfusion injury, peritonitis, colitis, blood vessel, pleuritis, asthma, gall-bladder fibrosis, septicemia, corneal injury, vasculogenesis, the tooth rim film is scorching, X 5189 causes hyperpathia and graft-right-host disease (GvHD) (Schwab and Serhan; Existing opinion on pharmacology, 2006,414-420).ALXR is also through confirming as the functional receptor of different number polypeptide, comprises the fragment of prion protein, derived from Human Immunodeficiency virus (HIV)-1 _LAIThe polypeptide of the gp120 of bacterial classification and amyloid-β 1-42 (Ab42) (consults people such as Le, Protein Pept Lett.; 2007,14,846-853); And morbidity (people such as Yazawa, FASEB J., 2001 of senile dementia (AD) have been pointed out to participate in several decisive modes; 15,2454-2462).ALXR sends the message cascade reaction for what the activation of scavenger cell and Microglial cell can cause that G protein mediated, and it can increase the creep of directivity cell, phagolysis and amboceptor and disengage.These incidents can be explained near monocytic replenishing senile plaque in the affected areas of AD brain, and Ab42 is excessively produced and accumulates in this zone.Though white cell is in the locational born host response that can be considered to harmful agent removing of accumulating of tissue injury, activated MNP also can disengage multiple material, such as superoxide anion, and it can be deleterious for neurone.Therefore, ALXR can mediate in the AD brain by the preparatory inflammation that Ab42 elicited and respond, and PD is more worsened.Also report human plain (HN); A kind of polypeptide with neuroprotective ability, the shared human ALXR of the Ab42 that can fasten with MNP and neuronal cell, and existing people points out that the competitiveness that the neuroprotective activity of HN is attributable to its ALXR occupies (people such as Ying; J.Immunol.; 2004,172,7078-7085).

The biological property that ALXR urges agent includes but not limited to the adjusting of unicellular/scavenger cell/Microglial/dendritic cell creep/activation, neutrophils creep/activation, lymphocyte activation effect, hyperplasia and differentiation adjusting, CYTOKINES production and/or the adjusting that disengages, preparatory inflammation amboceptor production and/or the adjusting that disengages, the immunoreactive adjusting of inflammation.

The present invention provides and fluoridizes aminotriazole derivatives, and it urges agent for the non-polypeptide of human ALX acceptor.This compound can be used for preventing or treats the ALX acceptor is regulated the disease that response is arranged, such as inflammatory diseases, obstructing airway disease, ThermoScript II virus infection, cardiovascular disorder, neural inflammation, nervous disorders, pain, the disease that Protein virus mediated and the illness (especially senile dementia) that amyloid mediated that allergic conditions, HIV mediated; In addition, it can be used for prevention or treatment autoimmune disease and adjusting immunne response (especially by the vaccination person of eliciting).

Compare with the aminotriazole derivatives that is disclosed among the WO 2009/077990; It also urges agent for the ALX acceptor, and the compound of the application's case represents the effect form through remarkable improvement when in covalent attachment detects, testing; Expect its with through relevant (the people Chem.Res.Toxicol. such as Evans of safety effect form of improvement; 2004,17,3-16).

Summary of the invention

Different embodiment of the present invention proposes hereinafter:

1) the present invention fluoridizes aminotriazole derivatives about formula (I),

Wherein

A representes heteroaryl, and wherein two of this heteroaryl tie points are 1, and 3-arranges;

R ¹The expression phenyl, it is without replacement, replaces or two replacements (it should be noted that without replacement or through single and replace) through single, and wherein substituting group independently is selected from the cohort of following composition: halogen, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy and dimethylamino; And

R ²Expression hydrogen, methyl, ethyl or cyclopropyl (it should be noted that hydrogen or methyl);

And the salt (particularly pharmacy acceptable salt) of this kind compound.

The hereinafter paragraph provides about the partly definition of group of various chemistry according to The compounds of this invention, and will as one man be applicable in whole patent specification and the request terms, only if there is the definition of statement clearly that broad or narrower definition are provided in addition.

That halogen one speech means is fluorine-based, chloro, bromo or iodo, is preferably fluorine-based, chloro or bromo, and most preferably is fluorine-based or chloro.

" heteroaryl " speech, independent or merging is used, and means 5-person's monocycle shape aromatic ring, contains the individual heteroatoms that independently is selected from oxygen, nitrogen and sulphur of 1,2 or 3 (being preferably 1 or 2).The embodiment of this kind heteroaryl is furyl 、 oxazolyl 、 isoxazolyl 、 oxadiazole base, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyrryl, imidazolyl, pyrazolyl and triazolyl.Preferred embodiment is that furyl (it should be noted that furans-2,5-two basic) 、 oxazolyls (Zhi gets Zhu meaning De Shi oxazole-2,4-two bases) and thiazolyl (it should be noted that thiazole-2,4-two bases).Most preferred embodiment is a furans-2,5-two Ji ， oxazoles-2,4-two bases, wherein 1; 1-two fluoro ethyls are connected to the 4-position, and thiazole-2,4-two bases, wherein 1; 1-two fluoro ethyls are connected to 4-position (and it is an oxazole-2 especially, 4-two bases, wherein 1,1-two fluoro ethyls are connected to the 4-position).More preferred embodiment is an oxazole-2,4-two bases, and wherein 1,1-two fluoro ethyls are connected to the 2-position.

" 1,3-arrange " speech when in the detailed description that is used in " A ", means to be connected to partly group and 1 of triazole-methyl, and two atoms of the heteroaryl of 1-two fluoro ethyls part group separately reach an atom; For example, if " A " expression furans-2,5-two bases are shown in the following texts and pictures of then substituent arrangement

2) further embodiment of the present invention is about according to embodiment 1) fluoridize aminotriazole derivatives, wherein

A represent to be selected from furyl (it should be noted that furans-2, the group of 5-two basic) 、 oxazolyls (Zhi gets Zhu meaning De Shi oxazole-2,4-two bases) and thiazolyl (it should be noted that thiazole-2,4-two bases), wherein two of this group tie points are 1,3-arranges;

R ¹The expression phenyl; It is for without replacing, replacing or two replace (it should be noted that without replacing or replacing through single) through single, and wherein substituting group independently is selected from the cohort of following composition: fluorine-based, chloro, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy and dimethylamino; And

R ²Expression hydrogen, methyl or ethyl (it should be noted that hydrogen or methyl);

And the salt (particularly pharmacy acceptable salt) of this kind compound.

3) further embodiment of the present invention is about according to embodiment 1) or 2) in each fluoridize aminotriazole derivatives, wherein

A representes furans-2,5-two bases (wherein 1,1-two fluoro ethyls preferably are connected to the 5-position), oxazole-2,4-two bases (wherein 1,1-two fluoro ethyls preferably are connected to the 4-position) or thiazole-2,4-two bases (wherein 1,1-two fluoro ethyls preferably are connected to the 4-position);

R ¹The expression phenyl, it be without replacing or through single replacement, wherein substituting group is selected from the cohort of following composition: fluorine-based, chloro, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy and dimethylamino; And

R ²Expression hydrogen or methyl;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

4) further embodiment of the present invention is about according to embodiment 1) or 2) in each fluoridize aminotriazole derivatives, wherein

And the salt (particularly pharmacy acceptable salt) of this kind compound.

5) further embodiment of the present invention is about according to embodiment 1) to 4) in each fluoridize aminotriazole derivatives, wherein

And the salt (particularly pharmacy acceptable salt) of this kind compound.

6) further embodiment of the present invention is about according to embodiment 1) to 4) in each fluoridize aminotriazole derivatives, wherein

A representes furyl (it should be noted that furans-2,5-two bases), and wherein two of this group tie points are 1, and 3-arranges;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

7) further embodiment of the present invention is about according to embodiment 1) to 5) in each fluoridize aminotriazole derivatives, wherein

A representes furans-2,5-two bases;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

8) further embodiment of the present invention is about according to embodiment 1) to 4) in each fluoridize aminotriazole derivatives, wherein

A Biao Shi oxazolyl (Zhi gets Zhu meaning De Shi oxazole-2,4-two bases), wherein two of this group tie points are 1, and 3-arranges;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

9) further embodiment of the present invention is about according to embodiment 1) to 5) in each fluoridize aminotriazole derivatives, wherein

A table shows oxazole-2,4-two bases (wherein 1,1-two fluoro ethyls preferably are connected to the 4-position);

And the salt (particularly pharmacy acceptable salt) of this kind compound.

10) further embodiment of the present invention is about according to embodiment 1) to 4) in each fluoridize aminotriazole derivatives, wherein

A representes thiazolyl (it should be noted that thiazole-2,4-two bases), and wherein two of this group tie points are 1, and 3-arranges;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

11) further embodiment of the present invention is about according to embodiment 1) to 5) in each fluoridize aminotriazole derivatives, wherein

A representes thiazole-2,4-two bases (wherein 1,1-two fluoro ethyls preferably are connected to the 4-position);

And the salt (particularly pharmacy acceptable salt) of this kind compound.

12) further embodiment of the present invention is about according to embodiment 1) to 11) in each fluoridize aminotriazole derivatives, wherein

R ¹The expression phenyl; It is for without replacing, replacing or two replace (it should be noted that without replacing or replacing through single) through single, and wherein substituting group independently is selected from the cohort of following composition: fluorine-based, chloro, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy and dimethylamino;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

13) further embodiment of the present invention is about according to embodiment 1) to 11) in each fluoridize aminotriazole derivatives, wherein

R ¹Expression is without substituted phenyl;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

14) further embodiment of the present invention is about according to embodiment 1) to 11) in each fluoridize aminotriazole derivatives, wherein

R ¹The expression phenyl, it replaces or two replacements (it should be noted that through single replacement) through single, and wherein substituting group independently is selected from the cohort of following composition: halogen, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy and dimethylamino;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

15) further embodiment of the present invention is about according to embodiment 1) to 11) in each fluoridize aminotriazole derivatives, wherein

R ¹The expression phenyl, it is replaced (and it should be noted that on the 3-position by the mono-substituted phenyl of fluorine-based, chloro, methyl or trifluoromethyl) by fluorine-based, chloro, methyl or trifluoromethyl list;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

16) further embodiment of the present invention is about according to embodiment 1) to 11) in each fluoridize aminotriazole derivatives, wherein

R ¹The expression phenyl, it is replaced (and it should be noted that 3-fluorophenyl or 3-chloro-phenyl-) by fluorine-based or chloro list;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

17) further embodiment of the present invention is about according to embodiment 1) to 11) in each fluoridize aminotriazole derivatives, wherein

R ¹The expression phenyl, it is replaced (and it should be noted that 3-methyl-phenyl) by the methyl list;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

18) further embodiment of the present invention is about according to embodiment 1) to 11) in each fluoridize aminotriazole derivatives, wherein

R ¹The expression phenyl, it is replaced (and it should be noted that 3-methoxyl group-phenyl) by the methoxyl group list;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

19) further embodiment of the present invention is about according to embodiment 1) to 11) in each fluoridize aminotriazole derivatives, wherein

R ¹The expression phenyl, it is replaced (and it should be noted that 3-trifluoromethyl-phenyl) by the trifluoromethyl list;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

20) further embodiment of the present invention is about according to embodiment 1) to 11) in each fluoridize aminotriazole derivatives, wherein

R ¹The expression phenyl, it is replaced (and it should be noted that 3-trifluoromethoxy-phenyl) by the trifluoromethoxy list;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

21) further embodiment of the present invention is about according to embodiment 1) to 11) in each fluoridize aminotriazole derivatives, wherein

R ¹The expression phenyl, it is replaced (and it should be noted that 3-dimethylamino-phenyl) by the dimethylamino list;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

22) further embodiment of the present invention is about according to embodiment 1), 2) or 4) to 21) in each fluoridize aminotriazole derivatives, wherein

R ²Expression hydrogen, methyl or ethyl;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

23) further embodiment of the present invention is about according to embodiment 1) to 21) in each fluoridize aminotriazole derivatives, wherein

R ²Expression hydrogen or methyl;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

24) further embodiment of the present invention is about according to embodiment 1) to 21) in each fluoridize aminotriazole derivatives, wherein

R ²Expression hydrogen;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

25) further embodiment of the present invention is about according to embodiment 1) to 21) in each fluoridize aminotriazole derivatives, wherein

R ²Expression methyl or ethyl (it should be noted that methyl);

And the salt (particularly pharmacy acceptable salt) of this kind compound.

26) further embodiment of the present invention is about according to embodiment 1) fluoridize aminotriazole derivatives, wherein

R ¹The expression phenyl, it be without replacing, replace or two replacements through single, wherein substituting group independently is selected from the cohort of following composition: fluorine-based, methyl and dimethylamino; And

R ²Expression hydrogen or methyl;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

27) further embodiment of the present invention is about according to embodiment 1) to 5), 8) or 12) to 26) in each fluoridize aminotriazole derivatives, wherein

A table shows oxazole-2,4-two bases, and wherein 1,1-two fluoro ethyls are connected to the 2-position;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

28) further embodiment of the present invention is about according to embodiment 1), 2), 4) to 12), 14) or 22) to 27) in each fluoridize aminotriazole derivatives, wherein

R ¹Expression 3-dimethylamino-4-fluorophenyl;

And the salt (particularly pharmacy acceptable salt) of this kind compound.

29) like embodiment 1) in defined preferred formula (I) compound be selected from the cohort of following composition:

Between 2-methyl-5--tolyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-phenyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

Between 2-methyl-5--tolyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

2-methyl-5-phenyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3,5-two fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-chloro-phenyl-)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-methoxyl group-phenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

2-cyclopropyl-5-phenyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

2-methyl-5-phenyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-fluorophenyl)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-chloro-phenyl-)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-fluorine-based-5-methyl-phenyl)-2-methyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-chloro-phenyl-)-2-methyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(4-fluorophenyl)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

Between 5--tolyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3,5-two fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-fluorophenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-methoxyl group-phenyl)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

Between 5--tolyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(4-fluorophenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-fluorine-based-5-methyl-phenyl)-2-methyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-phenyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-chloro-phenyl-)-2-methyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

2-ethyl-5-phenyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides; And

Between 2-methyl-5--tolyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

Or the salt of this kind compound (particularly pharmacy acceptable salt).

30) like embodiment 1) in defined further preferred formula (I) compound be selected from the cohort of following composition:

N-(2-((2-(1,1-two fluoro ethyls) oxazole-4-yl) methyl)-2H-1,2,3-triazole-4-yl)-2-methyl-5-(-tolyl) oxazole-4-carboxylic acid amides;

2-methyl-5-phenyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

5-(3-dimethylamino-4-fluorophenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides; And

5-(3-dimethylamino-4-fluorophenyl)-2-methyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides;

Or the salt of this kind compound (particularly pharmacy acceptable salt).

31) like embodiment 1) in defined most preferably formula (I) compound be:

Or its salt (particularly pharmacy acceptable salt).

The present invention also comprises with the isotropic substance mode and identifying, especially warp ²Formula (I) compound of H (deuterium) sign, this compound is identical with formula (I) compound, and each is had the same atoms preface only or a plurality of atoms, but atomic mass and the common different atomic substitutions of being found on natural of atomic mass.Identify with the isotropic substance mode, especially warp ²Formula (I) compound and the salt thereof of H (deuterium) sign, within the scope of the invention.Hydrogen is with than the heavy isotropic substance ²The replacement of H (deuterium) may cause big metabolism stability, and cause the in vivo half life of for example increase or the dosage requirement of reduction, maybe may cause the reduction of cytochrome P 450 enzymes to suppress, and cause the for example safety effect form of warp improvement.In an embodiment of the present invention, formula (I) compound does not identify with the isotropic substance mode, or it is only with one or more D atom sign.In an inferior embodiment, formula (I) compound does not identify with the isotropic substance mode fully.Formula (I) compound so that the isotropic substance mode identifies can similar method hereinafter described be processed, but uses the suitable isotropic substance modification of suitable reagent or starting substance.

" pharmacy acceptable salt " speech refers to nontoxicity, inorganic or organic acid and/or base addition salt, and document is " salt of alkaline drug is selected " for example, Iht.J.Pharm. (1986), 33,201-217.

Compound, salt, medical composition, disease etc. are being used under the situation of plural form, and it also means simplification compound, salt or its analogue.

According to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be suitable as medicament and use.Particular it; Formula (I) compound can be regulated the ALX acceptor; Be that it is useed the ALX acceptor as and urges agent; And can be used for preventing or treating the disease that the activation of ALX acceptor is had response, such as inflammatory diseases, obstructing airway disease, ThermoScript II virus infection, cardiovascular disorder, neural inflammation, nervous disorders, pain, the disease that Protein virus mediated and the illness (especially senile dementia) that amyloid mediated that allergic conditions, HIV mediated; In addition, it can be used for regulating immunity response (especially because of the vaccination person of eliciting).Formula (I) compound is particularly useful for prevention or treats following disease, such as inflammatory diseases, obstructing airway disease, allergic conditions, cardiovascular disorder, neural inflammation, nervous disorders, pain, the disease that Protein virus mediated and the illness (especially senile dementia) that amyloid mediated.

Particular it, according to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be applicable to that prevention or treatment are selected from the disease of inflammatory diseases, obstructing airway disease and allergic conditions.

That inflammatory diseases, obstructing airway disease and allergic conditions include but not limited to is a kind of, the disease and the illness of several or all following cohorts:

1) acute lung injury (ALI); Adult/acute dyspnea sign bunch (ARDS); COPD lung, air flue or tuberculosis (COPD, COAD or COLD) comprise chronic bronchitis or expiratory dyspnea related with it; Wind-puff; And the deterioration of the air flue irritation property that is caused because of the other medicines therapy, particularly other sucks pharmacotherapy.Inflammatory diseases, obstructing airway disease and allergic conditions especially comprise COPD, COAD and COLD.

2) other inflammatory diseases, obstructing airway disease and allergic conditions comprise the bronchitis of which kind of type no matter or origin.

3) other inflammatory diseases, obstructing airway disease and allergic conditions comprise the bronchiectasis and the Pneumonoconiosis of which kind of type no matter or origin.

4) other inflammatory diseases, obstructing airway disease and allergic conditions comprise the asthma of which kind of type no matter or origin, comprise that endogenous (nonallergic) asthma and asthma, occupational asthma that exogen (supersensitivity) asthma, gentle asthma, medium asthma, serious asthma, bronchitis asthma, motion are caused reach the asthma that behind infectation of bacteria, is caused.

5) in further embodiment, according to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be specially adapted to prevention or treatment inflammatory diseases.That inflammatory diseases comprises is a kind of, the disease and the illness of several or all following cohorts:

5a) particular it, inflammatory diseases refers to the neutrophils associated conditions, especially the neutrophils associated conditions of air flue comprises high neutrophils increase disease, because of it can influence air flue and/or lungs.Other neutrophils associated conditions also comprises tooth rim film inflammation, glomerule nephritis and gall-bladder fibrosis.

5b) other inflammatory diseases comprises tetter, such as psoriasis, contact dermatitis, atopic dermatitis, herpetic dermatitis, scleroderma, allergic angiitis, urticaria, lupus erythematosus and epidermis absent-mindedness.

5c) other inflammatory diseases disease or symptom also about having the inflammatory composition.Have the disease of inflammatory composition or disease and the symptom that symptom includes but not limited to influence eyes, for example (,) uveitis (front, centre and back),

sign bunch uveitis, binding film inflammation, keratoconjunctivitis sicca,

sign bunch keratoconjunctivitis sicca and spring binding film scorching (and especially scorching, the keratoconjunctivitis sicca of binding film and spring the binding film inflammation); Influence the disease of nose, comprise rhinitis and allergic rhinitis (and especially allergic rhinitis); And inflammatory diseases; Wherein involve autoimmune response; Or it has autoimmunization composition or etiology, such as systemic lupus erythematous, Ankylosing Spondylitis,

sign bunch,

sign bunch, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson sign bunch, primary aphthae tropicae, autoimmunization inflammatory bowel disease (for example ulcerative colitis and clone disease), endocrine ophthalmocace, chronic anaphylaxis pneumonia, the sclerosis of primary courage, keratoconjunctivitis sicca and vernal keratoconjunctivitis, tissue space pnemnofibrosis, psoriatic arthritis and glomerule nephritis (and especially systemic lupus erythematous, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson sign bunch, primary aphthae tropicae, autoimmunization inflammatory bowel disease (for example ulcerative colitis and clone disease), endocrine ophthalmocace, chronic anaphylaxis pneumonia, the sclerosis of primary courage, keratoconjunctivitis sicca and vernal keratoconjunctivitis, tissue space pnemnofibrosis, psoriatic arthritis and glomerule nephritis).

5d) other inflammatory diseases wherein involves autoimmune response, or it has autoimmunization composition or etiology, comprises rheumatic arthritis, struma lymphomatosa and I or type ii diabetes.

Moreover; According to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be applicable to that prevention or treatment organ or tissue transplantation repel; For example treat the recipient of cardiopulmonary, liver, kidney, pancreas, skin or the corneal graft of heart, lungs, merging; And prevention graft-right-host disease; For example bone marrow transplantation after, take place sometimes, particularly treat acute or chronic of the same race-with xenograft rejection, or the for example transplanting of islet cells of cell of generation Regular Insulin.

Moreover, according to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be applicable to prevention or the treatment ThermoScript II virus infection that HIV mediated.

That the ThermoScript II virus infection that HIV mediated includes but not limited to is a kind of, the disease and the illness that are caused because of HIV-1 and HIV-2 bacterial classification of several or all cohorts, this bacterial classification such as GUN-4v, GUN-7wt, AG204, AG206, AG208, HCM305, HCM308, HCM342, mSTD104 and HCM309.

Moreover, according to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be applicable to prevention or treatment cardiovascular disorder.

Cardiovascular disorder refers to one of cardiovascular tree (comprising heart) or various disease states, with the disease of subordinate organ.The disease of morbid state of cardiovascular tree and subordinate organ includes but not limited to the illness (myocardosis or myocarditis) of cardiac muscle; Such as primary cardiac myopathy; The metabolism myocardosis, it comprises diabetic subject's myocardosis, alcoholic cardiomyopathy, the myocardosis that medicine caused, exhausted courageous and upright myocardosis and hypertension myocardosis; The mainly congee appearance illness (huge vascular disease) of blood vessel, such as aorta, coronary artery, carotid artery, cerebrovascular artery, the Renal artery, bone artery, femoral artery are Ji the popliteal artery; The toxicity of little blood vessel, medicine causes and metabolism (comprising hypertension and/or mellitus) illness (microvascular disease); For example retina arteriole, renal glomerulus arteriole, neural blood vessel, heart arteriole, and eyes, kidney, heart and maincenter and the related Capillary bed of peripheral nervous system; And the spot of the congee appearance of main blood vessel damage breaks, such as aorta, coronary artery, carotid artery, cerebrovascular artery, the Renal artery, bone artery, femoral artery are Ji the popliteal artery.

Moreover, according to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be applicable to prevention or treat neural inflammation.Neural inflammation phalangeal cell sends activation or the Microglial activation approach and the response of the production of message molecule, neuroglial activation or neuroglia activation approach and response, inflammatory cells work element or chemical CYTOKINES, Astrocytic activation or stellate cell activation approach and response in advance, Microglial; The response of oxidisability pressure correlation; For example nitric oxide synthase production and nitrogen oxide are accumulated, the amyloid-beta deposition of the loss of acute phase protein, synaptophysin and postsynaptic density-95 protein (PSD-95) (composition of complementary stepwise reaction), the loss of cytoplasmic process engagement function or reduction, protein kinase active (for example dead related protein kinase is active), behavior shortage, cell damage (for example neuronal cell injury), necrocytosis (for example neuronal cell is dead) and/or amyloid spot.

Moreover, according to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be applicable to prevention or treatment nervous disorders.

Particular it; Nervous disorders includes but not limited to that the exhausted blood of epilepsy, apoplexy, brain, cerebral palsy, recurrence relax multiple sclerosis, carrying out property multiple sclerosis, optic neuromyelitis, clinical single sign bunch, AlperShi disease, amyotrophic lateral sclerosis (ALS), senile dementia, the dementia with LewyShi body, Rett sign bunch, Spinal injury, traumatic brain injury, trigeminal neuralgia, chronic inflammatory myelinoclasis polyneuropathy, Guillain-Barre sign bunch, tongue and nervus pharyngeus pain, BellShi paralysis, myasthenia gravis, muscular dystrophy, progressive muscular atrophy, the hereditary amyotrophy of carrying out property oblongata; The vertebra dish sign of deviating from, rupturing or prolapsing bunch; Cervical vertebra joint disease, nerve plexus disorder, thoracic outlet are destroyed sign bunch, Peripheral nerve disease, the decline of gentle cognitive power, cognitive power decline, senile dementia, Ba Jinshengshi disease and Huntington's disease, and (and especially epilepsy, apoplexy, the exhausted blood of brain, cerebral palsy, recurrence relax multiple sclerosis, carrying out property multiple sclerosis, AlperShi disease, amyotrophic lateral sclerosis (ALS), senile dementia, the dementia with LewyShi body, Rett sign bunch, Spinal injury, traumatic brain injury, trigeminal neuralgia, tongue and nervus pharyngeus pain, BellShi paralysis, myasthenia gravis, muscular dystrophy, progressive muscular atrophy, the hereditary amyotrophy of carrying out property oblongata; The vertebra dish sign of deviating from, rupturing or prolapsing bunch, cervical vertebra joint disease, nerve plexus disorder, thoracic outlet are destroyed sign bunch, Peripheral nerve disease, the decline of gentle cognitive power, cognitive power decline, senile dementia, Ba Jinshengshi disease and Huntington's disease).

Moreover, according to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be applicable to prevention or treatment pain.Pain includes but not limited to neuropathy originality pain; With some symptoms is example, such as pain, myelopathy or radiculopathy pain after pain, the amputation after diabetic subject's the neuropathy, postherpetic neuralgia, trigeminal neuralgia, painful mellitus polyneuropathy, apoplexy, unusual profile portion pain and like burning shape neurodynia sign bunch.

Moreover, according to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be applicable to prevention or the treatment disease that Protein virus mediated.The disease that Protein virus mediated; Also be called and transmit SE (TSE), include but not limited to Kuru disease, Gerstmann-

-Scheinker sign bunch (GSS), the familial insomnia (FFI) that causes death and Creutzfeldt-Jakob disease (CJD).

Moreover, according to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be applicable to the treatment illness that amyloid mediated.The illness that amyloid mediated is defined as because of amyloid or like amyloid protein and causes or disease related with it and illness.Cause or disease related with it and illness include but not limited to senile dementia (AD) because of amyloid or like amyloid protein, comprise it is characterized by disease or the symptom that cognitive memory capability is lost that for example gentle cognitive power weakens (MCI); Dementia with LewyShi body; DownShi sign bunch; Cerebral hemorrhage with amyloidosis.In another embodiment, cause or comprise dementia, amyotrophic lateral sclerosis (ALS), inclusion body myositis (IBM), adult beginning type mellitus and the old CARDIAC AMYLOID OSIS that paralysis on the carrying out property nuclear, amyloid light chain amyloidosis, familial amyloid shape albumen neuropathy, multiple sclerosis, Creutzfeld Jakob disease, Ba Jinshengshi are sick, HIV-is relevant (and dementia, amyotrophic lateral sclerosis (ALS), inclusion body myositis (IBM), adult beginning type mellitus and old CARDIAC AMYLOID OSIS that especially paralysis, multiple sclerosis, Creutzfeld Jakob disease, Ba Jinshengshi disease, HIV-are correlated with on the carrying out property nuclear) with its related disease and illness because of amyloid or like amyloid protein.

Moreover, according to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be applicable to the adjusting immunne response.

The adjusting of immunne response includes but not limited to give at least a antigen and at least a according to embodiment 1 so that sufferer is thrown) to 31) in each the compsn of formula (I) compound or its pharmaceutically-acceptable salts method that is the basis.In some cases, contain antigenic compsn and at first given by throwing, then throw give at least a according to embodiment 1) to 31) and in each formula (I) compound or the compsn of its pharmaceutically-acceptable salts.In other situation, contain antigenic compsn and given by throwing at last.Different compositions can be simultaneously, on the order closely or on the time, separately throw and give.These methods and compsn are provided, are used for treatment and epidemic prevention method (promptly adapting to and/or innately planned stimulation, raising, enhancing or the adjusting of immunne response).Certain benefits can comprise following one or more:

1) give in throwing at least a according to embodiment 1) to 31) and in each formula (I) compound or the acceleration immunne response behind its pharmaceutically-acceptable salts and the antigen, when giving antigen relatively the time with only throwing;

2) to a small amount of big susceptibility that can not cause one or more antigen (for example toxin or cause of disease) of strong immune response habitually; And

3) effective antitumor therapy more.

Moreover, according to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt inflammatory diseases that is applicable to the reduction of prevention or treatment gall-bladder fibrosis, pnemnofibrosis, pulmonary hypertension, wound healing, diabetic subject's ephrosis, the inflammation in transplanted tissue, caused because of the pathogenic organisms body.

According to embodiment 1) to 31) in each formula (I) compound or its pharmacy acceptable salt be particularly useful for prevention or treatment disease, be selected from disease and illnesss a kind of, several or all following cohorts:

1) inflammatory diseases, obstructing airway disease and allergic conditions, for example acute lung injury (ALI); Adult/acute dyspnea sign bunch (ARDS); COPD lung, air flue or tuberculosis (COPD, COAD or COLD) comprise chronic bronchitis or expiratory dyspnea related with it; And the no matter asthma of which kind of type or origin, comprise that endogenous (nonallergic) asthma and asthma, occupational asthma that exogen (supersensitivity) asthma, gentle asthma, medium asthma, serious asthma, bronchitis asthma, motion are caused reach asthma (and the especially acute lung injury (ALI) that behind infectation of bacteria, is caused; Adult/acute dyspnea sign bunch (ARDS); And the no matter asthma of which kind of type or origin, comprise that endogenous (nonallergic) asthma and asthma, occupational asthma that exogen (supersensitivity) asthma, gentle asthma, medium asthma, serious asthma, bronchitis asthma, motion are caused reach the asthma that behind infectation of bacteria, is caused);

2) inflammatory diseases, such as the neutrophils associated conditions of neutrophils associated conditions, especially air flue comprise high neutrophils increase disease, because of it can influence air flue and/or lungs; The tooth rim film is scorching; The glomerule nephritis; The gall-bladder fibrosis; And tetter, such as psoriasis, contact dermatitis, atopic dermatitis, herpetic dermatitis, scleroderma, allergic angiitis, urticaria, lupus erythematosus and epidermis absent-mindedness;

3) have the disease of inflammatory composition, for example influence the disease and the symptom of eyes, for example (,) binding film is scorching, keratoconjunctivitis sicca and spring binding film scorching; Inflammatory diseases, wherein for involving autoimmune response, or it has autoimmunization composition or etiology; And autoimmunization inflammatory bowel disease (for example ulcerative colitis and clone disease);

4) the ThermoScript II virus infection that HIV mediated; The disease and the illness that are for example caused because of HIV-1 and HIV-2 bacterial classification, this bacterial classification such as GUN-4v, GUN-7wt, AG204, AG206, AG208, HCM305, HCM308, HCM342, mSTD104 and HCM309;

5) neural inflammation; Its phalangeal cell sends that the message molecule is produced, activation or the Microglial activation approach and the response of neuroglial activation or neuroglia activation approach and response, inflammatory cells work element or chemical CYTOKINES, Astrocytic activation or stellate cell activation approach and response in advance, Microglial; The response of oxidisability pressure correlation, such as the amyloid-beta of amyloid spot deposition;

6) nervous disorders, such as apoplexy, the exhausted blood of brain, senile dementia and Ba Jinshengshi are sick;

7) disease that Protein virus mediated; Also be called and can transmit SE (TSE), such as Kuru disease, Gerstmann-

-Scheinker sign bunch (GSS), the familial insomnia (FFI) that causes death and Creutzfeldt-Jakob disease (CJD);

8) illness that amyloid mediated;

9) gall-bladder fibrosis, wound healing and the inflammatory diseases that caused because of the pathogenic organisms body.

The present invention is also about according to embodiment 1) to 31) in each the purposes of formula (I) compound on the preparation medical composition, this medical composition is used to treat and/or prevents the mentioned disease of preceding text.

The present invention is also about according to embodiment 1) to 31) in each the pharmaceutically-acceptable salts of formula (I) compound, and medical composition and prescription.

Medical composition according to the present invention contains at least a according to embodiment 1) to 31) in each formula (I) compound (or its pharmacy acceptable salt) as promoting agent, and supporting agent and/or thinner and/or the adjuvant selected for use according to circumstances.

According to embodiment 1) to 31) in each formula (I) compound and pharmacy acceptable salt thereof can be used as medicament and use, for example be the form of medical composition, supply to use through the intestines dispensing through intestines or non-.

The manufacturing of medical composition can any those skilled in the art be familiar with mode reach and (consult Remington for example, pharmacy science and practice; The 21st edition (2005); The 5th partly, " medicine is made " [being published by Lippincott Williams&Wilkins]), its mode is to cause described formula (I) compound and pharmacy acceptable salt thereof; Go up valuable material according to circumstances and with other treatment; Become and cover the human relations types of administration, being accompanied by that the treatment of suitable nontoxicity inertia goes up can compatible solid or liquid carrier material, and uses medical adjuvant always if need then comprise.

The present invention is also about the method for mentioned disease or illness among a kind of prevention or treatment this paper, it comprise to sufferer throw give the medicinal activity amount according to embodiment 1) to 31) and in each formula (I) compound or its pharmacy acceptable salt.

Should understand in this article the salt (and especially pharmacy acceptable salt) of any denotion of formula (I) compound also being censured this kind compound, by suitably with expedient mode.About the indicated priority of formula (I) compound, be applicable to the salt and the pharmacy acceptable salt of (necessary change) formula (I) compound certainly in addition.Same case is applicable to these compounds as medicament, contains the medical composition of these compounds as active major ingredient, or the purposes of these compounds on medicament is made, and this medicament is used for treatment according to disease of the present invention.

Only if use about temperature, otherwise place the preceding term " about " of numerical value " X " (perhaps " approximately "), deduct 10%X at the application's case middle finger from X and extend to the interval that X adds 10%X, and refer to that preferably deducting 5%X from X extends to the interval that X adds 5%X.In the particular case of temperature, place the preceding term " about " of temperature " Y " (perhaps " approximately "), deduct 10 ℃ at the application's case middle finger from temperature Y and extend to the interval that Y adds 10 ℃, and refer to that preferably deducting 5 ℃ from Y extends to the interval that Y adds 5 ℃.In addition, " room temperature " in this paper, used (rt) speech refers to about 25 ℃ temperature.

Formula (I) compound can be by the method that hereinafter gave, the method for being given in the embodiment, or by the similar approach manufacturing.The optimum reaction conditions can change along with employed specific reactants or solvent, but this kind condition can be measured by customary optimization procedure by those skilled in the art.

If do not indicate then general group A, R in addition ¹And R ²All like definition about formula (I).Employed other abbreviation defines in the experiment paragraph.General radicals R ^u, in the time of in being used in hereinafter structure 6, expression hydrogen or methyl.General radicals R ^x, in the time of in being used in hereinafter structure 4, expression methyl or ethyl, or two R ^xForm ethane-1 together, 2-two basic abutments.General carboxyl-protecting group R; In for example being used in hereinafter structure 5, in graphic, and in experiment general procedure partly the time; Expression methyl, ethyl, just-propyl group, sec.-propyl, just-butyl, isobutyl-, second-butyl or the tertiary butyl, and be preferably methyl or ethyl.General group Si ^PG, in the time of in being used in hereinafter structure 6, expression appropriate Si alkyl protection base, such as TMS, TIPS, TBDMS or TBDPS are preferably TBDMS.

The reaction of alcohols and methylsulfonyl chloride can cause the formation of indivedual muriates or indivedual methanesulfonic salt derivatives, decides according to employed reaction conditions; Convention in this skill, the little change on this kind reaction conditions can have influence for the result of this reaction; What should understand is, two kinds of reagent, and muriate and methane sulfonates can be used as electrophilic reagent and are used in the reaction that hereinafter discusses under normal circumstances.

In some cases, general group A, R ¹And R ²Assembling shown in maybe be with hereinafter graphic is incompatible, and therefore needs utilize and protect basic (PG).Protect be utilized as (the consulting for example " the protection base in the organic synthesis ", T.W.Greene, P.G.M.Wuts, Wiley-Interscience, 1999) known in this field of base.As far as the purpose of this discussion, will suppose that this kind protection base in position goes up on demand.

A. final product is synthetic

Hereinafter paragraph A) for describing the general method of preparation formula (I) compound.

A) formula (I) compound can be made the amine of self-structure 1, and its mode is and suitable carboxylic acid chloride, under the temperature of about room temperature, at appropriate solvent such as CH ₂Cl ₂In, in alkali such as Et ₃There are reaction down in N or DIPEA.Suitably the carboxylic acid chloride can make under the temperature of about room temperature from its corresponding structure 7 carboxylic acids, and its mode is and reagent, such as the chlorination oxalyl, exists down in DMF, in appropriate solvent such as toluene, reacts.Perhaps, the amine of structure 1 can with the carboxylic acid of appropriate configuration 7, use standard amide coupling condition, such as EDC/HOBt/DMAP, TBTU, HBTU or PyBOP, in alkali such as DIPEA or Et ₃N exists down, under the temperature of about room temperature, in appropriate solvent such as CH ₂Cl ₂Middle coupling, and get formula (I) compound.

The compound of structure 1 can get the compound of self-structure 2 via the reductive action of nitro, and its mode is a hydrogenization, exist down in metal catalyst, such as Pd/C, Pt/C or PtO ₂, under the temperature of about room temperature, in appropriate solvent such as MeOH or EtOH, or by with metal, such as iron, at solvent mixture such as H ₂Among the O/EtOH, there is down the reductive action under room temperature to 95 ℃ range temperature in ammonium chloride.

B. intermediate is synthetic

The compound of structure 2 can be made the compound of self-structure 3; Its mode is to use fluorizating agent, and for example (diethylin) sulfur trifluoride or (two (2-methoxy ethyl) amino) sulfur trifluoride exist down in the alcohol such as the EtOH of catalytic amount; In solvent such as toluene, the fluorization under about 60 ℃ of temperature.

Perhaps, the compound of structure 2 can be via making Ms-O-CH ₂-A-CF ₂-CH ₃Or Cl-CH ₂-A-CF ₂-CH ₃With 4-nitro-2H-[1,2,3] triazole (people's organic formulations and program 2 (2) such as T.E.Eagles, 117-119,1970; P.N.Neuman J.Heterocycl.Chem.8,51-56,1971), in alkali such as K ₂CO ₃Or Cs ₂CO ₃Exist down, in solvent such as acetone or AcCN, reaction under the temperature of about room temperature or 80 ℃ and process (interpolation or do not add Tetrabutyl amonium bromide); If A Biao Shi oxazole-2; 4-two bases, then Shi is Yonged the oxazole verivate, such as methanesulfonic (2-(1; 1-two fluoro ethyls) methyl esters oxazole-4-yl), or formula Ms-O-CH ₂-A-CF ₂-CH ₃Or Cl-CH ₂-A-CF ₂-CH ₃Another kind of suitably reagent.Perhaps, reaction can exist down in alkali such as DIPEA, in solvent such as DMF, acetone or both mixtures, under the temperature of about room temperature or 50 ℃, carries out.

The compound of structure 3 can be via making Ms-O-CH ₂-A-C (O)-CH ₃Or Cl-CH ₂-A-C (O)-CH ₃With 4-nitro-2H-[1,2,3] triazole (people's organic formulations and program 2 (2) such as T.E.Eagles, 117-119,1970; P.N.Neuman J.Heterocycl.Chem.8,51-56,1971), in alkali such as K ₂CO ₃Or Cs ₂CO ₃Exist down, in solvent such as acetone or AcCN, reaction under the temperature of about room temperature or 80 ℃ and process (adding or do not add Tetrabutyl amonium bromide) is represented furans-2 as if A; 5-two bases then use furan derivatives, such as 1-(5-chloro methyl-furans-2-yl)-ethyl ketone; Or if A Biao Shi oxazole-2,4-two bases, then Shi is Yonged the oxazole verivate; Such as methanesulfonic 4-ethanoyl-oxazoles-2-base methyl esters, or if A Biao Shi isoxazole-2,4-two bases; Then use Isoxazole derivative, such as 1-(5-chloro methyl-isoxazole-3-bases)-ethyl ketone, or formula Ms-O-CH ₂-A-C (O)-CH ₃Or Cl-CH ₂-A-C (O)-CH ₃Another kind of suitably reagent.Perhaps, reaction can exist down in alkali such as DIPEA, in solvent such as DMF, acetone or both mixtures, under the temperature of about room temperature or 50 ℃, carries out.

Perhaps, the compound of structure 3 can be removed protection via the ketal that makes structure 4, and use standard conditions and process, for example:

■ uses acid, such as rare HCl aqueous solution, in solvent such as THF, under the temperature of about room temperature; Or

■ uses SCX silica gel, in solvent such as MeOH; Or

■ uses the acid of silica gel bonded, such as toluenesulphonic acids, in solvent such as MeOH; Or

■ uses acid, such as formic acid, in solvent such as water, about 0 ℃ to the temperature of about 50 ℃ of scopes.

Perhaps, the compound of structure 3 can be by following order, and the individual compound of self-structure 5 begins and processes:

The ester of ■ structure 5 is reduced into its alcohol accordingly, under the standard reductive condition, uses reagent, such as NaBH ₄, in solvent such as MeOH, under the temperature of about room temperature, perhaps, use reagent, such as DiBAL, in solvent such as THF, making an appointment with-78 ℃ to the temperature of room temperature range;

■ alcohol be oxidized to its corresponding aldehyde, under the standard oxidation condition, use reagent, such as MnO ₂, pyridinium chloro-chromate or NMO/TPAP, in solvent such as AcCN or CH ₂Cl ₂In, under the temperature of about room temperature;

■ adds alkyl Grignard reagent, under subambient temperature, (is preferably-78 ℃ approximately), in solvent such as THF, perhaps, adds trialkylaluminium reagent, under about 0 ℃ temperature, in solvent such as CH ₂Cl ₂In, its corresponding secondary alcohol is provided; And

The oxygenizement of ■ alcohol under the standard oxidation condition, is used reagent, such as TPAP/NMO or MnO ₂, in solvent such as CH ₂Cl ₂Or among the AcCN, under the temperature of about room temperature, so that the compound of structure 3 to be provided.

Perhaps, the compound of structure 3 can be by following order, self-structure 6 (R ^uThe expression methyl) individual compound begins and processes:

Fluorizating agent is used in the removal protection of ■ silyl ether verivate, such as TBAF, in solvent such as THF, under the temperature of about room temperature; With

■ alcohol be oxidized to its corresponding ketone, under the standard oxidation condition, use reagent, such as MnO ₂, pyridinium chloro-chromate or NMO/TPAP, in solvent such as AcCN or CH ₂Cl ₂In, under the temperature of about room temperature;

Perhaps, the compound of structure 3 can be by following order, self-structure 6 (R ^uExpression hydrogen) individual compound begins and processes:

Fluorizating agent is used in the removal protection of ■ silyl ether verivate, such as TBAF, in solvent such as THF, under the temperature of about room temperature;

The compound of structure 4 can be via making Ms-O-CH ₂-A-C (OR ^x) ₂-CH ₃Or Cl-CH ₂-A-C (OR ^x) ₂-CH ₃With 4-nitro-2H-[1,2,3] triazole, in alkali such as K ₂CO ₃Or Cs ₂CO ₃Exist down, in solvent such as acetone or AcCN, reaction under the temperature of about room temperature or 80 ℃ and process (adding or do not add Tetrabutyl amonium bromide) is represented furans-2 as if A; 5-two bases then use the furan derivatives through due care, such as 2-(5-chloro methyl-furans-2-yl)-2-methyl-[1,3] dioxolane; Or if A representes fen-2,5-two bases then use the fen verivate through due care, such as 2-(5-chloro methyl-fen-2-yl)-2-methyl-[1; 3] dioxolane, or if A representes thiazole-2,4-two bases then use the thiazole derivative through due care; Such as methanesulfonic 4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl esters or 4-chloro methyl-2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole, or if A representes fen-2; 4-two bases then use the fen verivate through due care, such as 2-(4-chloro methyl-fen-2-yl)-2-methyl-[1,3] dioxolane or 2-(5-chloro methyl-fen-3-yl)-2-methyl-[1; 3] dioxolane, or if A representes thiazole-2,5-two bases; Then use thiazole derivative through due care, such as methanesulfonic 5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl esters or 5-chloro methyl-2-(2-methyl-[1; 3] dioxolane-2-yl)-thiazole, or if A Biao Shi oxazole-2,5-two bases; Then use through due care De oxazole verivate, such as 2-chloro methyl-5-(2-methyl-[1,3] dioxolane-2-yl)-oxazoles or formula Ms-O-CH ₂-A-C (OR ^x) ₂-CH ₃Or Cl-CH ₂-A-C (OR ^x) ₂-CH ₃Another kind of suitably reagent.Perhaps, reaction can exist down in alkali such as DIPEA, in solvent such as DMF, acetone or both mixtures, under the temperature of about room temperature or 50 ℃, carries out.

The compound of structure 5 can similar structures 4 mode, via making Ms-O-CH ₂-A-C (O)-O-R or Cl-CH ₂-A-C (O)-O-R and 4-nitro-2H-[1,2,3] triazole is reacted and is processed, and uses the for example commercial 5-chloro methyl-furans-2-carboxylate methyl ester that gets (A representes furans-2,5-two bases) or 4-chloro methyl-thiazole-2-carboxylic acid, ethyl ester (A representes thiazole-2,4-two bases).

The compound of structure 6 can similar structures 4 mode, via making Ms-O-CH ₂-A-CH (OSi ^PG)-R ^uOr Cl-CH ₂-A-CH (OSi ^PG)-R ^uProcess with the reaction of the commercial 4-nitro-2H-that gets [1,2,3] triazole; If A Biao Shi oxazole-2,5-two bases, then Shi is Yonged the oxazole verivate; Such as 2-[1-(tertiary butyl-dimethyl--silanyloxy base)-ethyl]-5-chloro methyl-oxazoles, or if A Biao Shi oxazole-2,4-two bases; Then use through due care De oxazole verivate, such as methanesulfonic 2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-oxazoles-4-base methyl esters or formula Ms-O-CH ₂-A-CH (OSi ^PG)-R ^uOr Cl-CH ₂-A-CH (OSi ^PG)-R ^uAnother kind of suitably reagent.

1-(5-chloro methyl-furans-2-yl)-ethyl ketone can use following order to process: a) the commercial 5-methylol that gets-2 furan carboxyaldehyde uses 3, and 4-dihydro-2H-pyrans exists down in the toluene-4-sulfonic acid pyridinium salt, at solvent such as CH ₂Cl ₂In protection; B) aldehyde uses for example methylmagnesium-chloride, in solvent such as THF, and the methylation under about 0 ℃ of temperature; C) formed secondary alcohol uses oxygenant, such as MnO ₂, in solvent such as CH ₂Cl ₂In, the oxygenizement under about 45 ℃ of temperature; D) the protection base uses acid, such as Amberlyst 15, in appropriate solvent such as MeOH, and removing under about 35 ℃ of temperature; And e) alcohol uses for example Ms-Cl, in alkali such as Et ₃N and DMAP exist down, at solvent such as CH ₂Cl ₂In, the chlorization under the temperature in scope from 0 ℃ to room temperature.

2-(5-chloro methyl-furans-2-yl)-2-methyl-[1,3] dioxolane can use following order to process: a) the commercial 1-furans-2-base-ethyl ketone that gets is in trimethyl orthoformate and catalyzer such as LiBF ₄Exist down, in solvent such as terepthaloyl moietie, the protection under about 95 ℃ of temperature; B) with organolithium reagent, for example just-butyllithium, in solvent such as THF, the lithiumation effect under about-78 ℃ of temperature is with continuous interpolation the after the DMF; C) with reductive agent, such as NaBH ₄, in solvent such as MeOH, the reductive action under about 0 ℃ of temperature; And d) alcohol uses for example methylsulfonyl chloride, in alkali such as Et ₃N and DMAP exist down, at solvent such as CH ₂Cl ₂In, the chlorization under about 0 ℃ of temperature.

1-(5-chloro methyl-isoxazole-3-bases)-ethyl ketone can use following order to process: a) 5-methylol-isoxazoles-3-carboxylic acid, ethyl ester uses for example chlorination tertiary butyl dimethylsilane, has down the protection in solvent such as THF in alkali such as imidazoles; B) with reductive agent, for example (,) DiBAL, in solvent such as THF, the reductive action under subambient temperature; C) alcohol uses reagent under the standard oxidation condition, such as MnO ₂, in solvent such as AcCN, the oxygenizement under the temperature of about room temperature; D) add trimethylaluminium, under about 0 ℃ temperature, in solvent such as CH ₂Cl ₂In; E) alcohol uses reagent under the standard oxidation condition, such as MnO ₂, in solvent such as AcCN, the oxygenizement under the temperature of about room temperature; F) the silyl ether verivate uses fluorizating agent, such as TBAF, in solvent such as THF, and the removal protection under the temperature of about room temperature; And g) alcohol uses for example methylsulfonyl chloride, in alkali such as Et ₃N and DMAP exist down, at solvent such as CH ₂Cl ₂In, the chlorization under about 0 ℃ of temperature.

2-(5-chloro methyl-fen-2-yl)-2-methyl-[1,3] dioxolane can use following order to process: a) the commercial 2-methyl that gets-2-fen-2-base-[1,3] dioxolane is with organolithium reagent; For example just-and butyllithium, in N, N; N ', N '-tetramethyl--quadrol exist down, in solvent such as THF; Lithiumation effect under about-78 ℃ of temperature is with continuous interpolation the after the DMF; B) with reductive agent, such as NaBH ₄, in solvent such as MeOH, the reductive action under about 0 ℃ of temperature; And c) alcohol uses for example methylsulfonyl chloride, in alkali such as Et ₃N and DMAP exist down, at solvent such as CH ₂Cl ₂In, the chlorization under about 0 ℃ of temperature.

Methanesulfonic 4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl esters can be processed by following order: a) commercial get 2,4-two bromo-thiazole and organolithium reagents; For example just-butyllithium; In solvent such as ether, the reaction under about-78 ℃ of temperature, and with N; N-dimethyl--methane amide ,-78 ℃ to the room temperature range temperature after continuous formylation effect; B) with reductive agent, such as NaBH ₄, in solvent such as MeOH, the reductive action under the temperature of about room temperature; C) alcohol uses chlorination tertiary butyl dimethylsilane, has down the protection in solvent such as methylene dichloride in alkali such as imidazoles; D) through the alcohol and the organolithium reagent of protection, for example just-butyllithium, in solvent such as ether, the reaction under-78 ℃ of temperature approximately, and with DMAC N,N is continuing acetylizing at-78 ℃ after to the room temperature range temperature; E) in trimethyl orthoformate and catalyzer such as LiBF ₄Exist down, in solvent such as terepthaloyl moietie, the ketal under about 95 ℃ of temperature forms; F) siloyl group protection base is under standard conditions, such as TBAF, and in solvent such as THF, the removal under about room temperature or 0 ℃ of temperature is protected; And g) use reagent, such as methylsulfonyl chloride, at solvent such as CH ₂Cl ₂In, in alkali such as Et ₃N and DMAP exist down, the mesylation under about 0 ℃ of temperature.

2-(4-chloro methyl-fen-2-yl)-2-methyl-[1,3] dioxolane can be by about 2-(5-chloro methyl-furans-2-yl)-2-methyl-said processing of [1,3] dioxolane, but begin with the commercial 1-that gets (4-bromo-2-thienyl)-second-1-ketone.

4-chloro methyl-thiazole-2-carboxylic acid, ethyl ester can be processed by following order: a) commercial ethyl oxamide that gets and LawessonShi reagent, and in solvent such as toluene, the reaction under about 80 ℃ of temperature; With b) with 1, the 3-Dichloro acetone, in solvent such as toluene, the cyclic action under about 110 ℃ of temperature.

4-chloro methyl-2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole can be followed in trimethyl orthoformate and catalyzer such as LiBF by about the synthetic described order of structure 3 compounds of self-structure 5 compounds ₄Exist down, in solvent such as terepthaloyl moietie, the ketal under about 90 ℃ of temperature forms, and system is from 4-chloro-methyl-thiazole-2-carboxylic acid, ethyl ester.

Methanesulfonic 5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl esters can be processed by following order: a) commercial 2-bromo-thiazole-5-carboxylic formaldehyde and the trimethylaluminium that gets, and in solvent such as methylene dichloride, the reaction under about 0 ℃ of temperature; B) with oxygenant, such as MnO ₂, in solvent such as acetonitrile, the oxygenizement under the temperature of about room temperature; C) in trimethyl orthoformate and catalyzer such as LiBF ₄Exist down, in solvent such as terepthaloyl moietie, the ketal under about 95 ℃ of temperature forms; D) with organolithium reagent, for example just-butyllithium, in solvent such as ether, the lithiumation effect under about-78 ℃ of temperature, and with N, continuous formylation effect after the dinethylformamide; E) with reductive agent, such as NaBH ₄, in solvent such as MeOH, the reductive action under the temperature of about room temperature; And f) use reagent, such as methylsulfonyl chloride, at solvent such as CH ₂Cl ₂In, in alkali such as Et ₃N and DMAP exist down, the mesylation under about 0 ℃ of temperature.

5-chloro methyl-2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole can be processed by following order: a) commercial the 2-bromo-thiazole that gets-5-carboxylic formaldehyde is with reductive agent, such as NaBH ₄, in solvent such as MeOH, the reductive action under the temperature of about room temperature; B) alcohol uses chlorination tertiary butyl dimethylsilane, at solvent such as CH ₂Cl ₂In, the protection under alkali such as imidazoles existence; C) with organolithium reagent, for example just-butyllithium, in solvent such as ether, the lithiumation effect under about-78 ℃ of temperature, and with continuous acetylizing after the DMAC N,N; D) in trimethyl orthoformate and catalyzer such as LiBF ₄Exist down, in solvent such as terepthaloyl moietie, the ketal under about 95 ℃ of temperature forms; E) the silyl ether verivate uses fluorizating agent, such as TBAF, in solvent such as THF, and the removal protection under the temperature of about room temperature; And f) use reagent, such as methylsulfonyl chloride, at solvent such as CH ₂Cl ₂In, in alkali such as Et ₃N and DMAP exist down, the chlorization under about 0 ℃ of temperature.

2-(5-chloro methyl-fen-3-yl)-2-methyl-[1,3] dioxolane can be by (2-methyl-[1,3] dioxolane-2-yl)-thiazole is said to be processed about 5-chloro methyl-2-, but begins with the commercial 4-bromo-fen that gets-2-carboxylic formaldehyde.

Methanesulfonic 4-ethanoyl-oxazoles-2-base methyl esters can be processed by following order: a) oxazole forms, and makes the commercial 3-phenyl-acrylic amide that gets and 3-bromo-2-ketone group-ethyl propionate, in alkali such as NaHCO ₃Exist down, in solvent such as THF, under about 60 ℃ temperature, react; B) use the NaIO that for example silica gel carried ₄With metal misfit thing, such as RuCl ₃Hydrate, in solvent such as methylene dichloride, the oxidisability division under the temperature of about room temperature; C) with reductive agent, such as NaBH ₄, in solvent such as EtOH, the reductive action under about 0 ℃ of temperature; D) alcohol uses chlorination tertiary butyl dimethylsilane, at solvent such as CH ₂Cl ₂In, the protection under alkali such as imidazoles existence; E) with reductive agent, such as DiBAL, in solvent such as CH ₂Cl ₂In, at the aldehyde that is reduced into of making an appointment with under-78 ℃ of temperature; F) and trimethylaluminium, in solvent such as methylene dichloride, the reaction under about 0 ℃ of temperature; G) with oxygenant, such as MnO ₂, in solvent such as acetonitrile, the oxygenizement under the temperature of about room temperature; H) the silyl ether verivate uses fluorizating agent, such as TBAF, in solvent such as THF, and the removal protection under the temperature of about room temperature; And i) use reagent, such as methylsulfonyl chloride, at solvent such as CH ₂Cl ₂In, in alkali such as Et ₃N and DMAP exist down, the mesylation under about 0 ℃ of temperature.

Methanesulfonic 2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-oxazoles-4-base methyl esters can be processed by following order: a) oxazole forms, and makes the commercial 3-phenyl-acrylic amide that gets and 3-bromo-2-ketone group-ethyl propionate, in alkali such as NaHCO ₃Exist down, in solvent such as THF, under about 60 ℃ temperature, react; B) use the NaIO that for example silica gel carried ₄With metal misfit thing, such as RuCl ₃Hydrate is in solvent such as CH ₂Cl ₂In, the oxidisability division under the temperature of about room temperature; C) with reductive agent, such as NaBH ₄, in solvent such as EtOH, the reductive action under about 0 ℃ of temperature; D) alcohol uses chlorination tertiary butyl dimethylsilane, at solvent such as CH ₂Cl ₂In, the protection under alkali such as imidazoles existence; E) with reductive agent, such as DiBAL, in solvent such as THF, under about 0 ℃ of temperature, be reduced into alcohol; And f) use reagent, such as methylsulfonyl chloride, at solvent such as CH ₂Cl ₂In, in alkali such as Et ₃N and DMAP exist down, the mesylation under about 0 ℃ of temperature.

2-[1-(tertiary butyl-dimethyl--silanyloxy base)-ethyl]-5-chloro methyl-oxazoles can use following order to process: but a) commercial De De oxazole and organomagnesium reagent; Such as isopropylmagnesium chloride; In solvent such as THF; Reacting under-15 ℃ the temperature approximately, and with N-methoxyl group-N-methylacetamide ,-15 ℃ of follow-up acetylizings to the room temperature range temperature; B) with reductive agent, such as NaBH ₄, in solvent such as MeOH, the reductive action under the temperature of about room temperature; C) alcohol uses chlorination tertiary butyl dimethylsilane, has down the protection in solvent such as THF in alkali such as imidazoles; D) through the alcohol and the organolithium reagent of protection, such as tert-butyl lithium, in solvent such as THF, the reaction under-78 ℃ to-40 ℃ range temperature, and with N, N-dimethyl--methane amide continues the formylation effect at-78 ℃ after to the room temperature range temperature; E) with reductive agent, such as NaBH ₄, in solvent such as MeOH, the reductive action under the temperature of about room temperature; And f) use reagent, such as methylsulfonyl chloride, at solvent such as CH ₂Cl ₂In, in alkali such as Et ₃N and DMAP exist down, the chlorization under about 0 ℃ of temperature.

2-chloro methyl-5-(2-methyl-[1; 3] dioxolane-2-yl)-oxazoles can use following order to process: but a) commercial De De oxazole with organolithium reagent, for example just-butyllithium, in solvent such as THF; Lithiumation effect under about-78 ℃ of temperature is with continuous interpolation the after the DMF; B) with reductive agent, such as NaBH ₄, in solvent such as MeOH, the reductive action under about 0 ℃ of temperature; C) alcohol uses chlorination tertiary butyl dimethylsilane, has down the protection in solvent such as THF in alkali such as imidazoles; D) with organolithium reagent, such as tert-butyl lithium, in solvent such as THF, the lithiumation effect under-78 ℃ to-40 ℃ range temperature, and with DMF is-78 ℃ of follow-up formylation effects to the room temperature range temperature; E) and trimethylaluminium, in solvent such as methylene dichloride, the reaction under about 0 ℃ of temperature; F) with oxygenant, such as MnO ₂, in solvent such as acetonitrile, the oxygenizement under the temperature of about room temperature; G) the siloyl group protection is based on trimethyl orthoformate and catalyzer such as LiBF ₄Exist down, in solvent such as terepthaloyl moietie, the ketal under about 95 ℃ of temperature forms and removes protection; And h) alcohol uses for example methylsulfonyl chloride, in alkali such as Et ₃N and DMAP exist down, at solvent such as CH ₂Cl ₂In, the chlorization under about 0 ℃ of temperature.

Methanesulfonic (2-(1,1-two fluoro ethyls) oxazole-4-yl) methyl esters can use the order described in the experiment partly to process.

The acids of structure 7 is commercial getting, and for known in this field, or processes according to method hereinafter described.

The compound of structure 7, wherein R ²Expression Me can process described in graphic 1, and its mode is the aqueous solution that makes 3-ketone group-propanoate ester derivatives and Sodium Nitrite, has reaction down in acid such as Glacial acetic acid min. 99.5.Oxime in the metal chloride of acid such as Glacial acetic acid min. 99.5 and catalytic amount such as the subsequent transition under mercury chloride or zinc chloride and the zinc powder existence, then is the cyclic action under dehydration conditions with acetic anhydride; For example the dichloride thionyl in chloroform, then uses the saponification of currently known methods in this skill for the ester functional group; For example with alkali; For example NaOH handles in solvent or solvent mixture such as ethanol/water or THF, obtains desired acid derivative.Indivedual 3-ketone group-propanoate ester derivatives are commercial get or known in this field.

Graphic 1: oxazole synthesizes (1)

Perhaps, the compound of structure 7 can be processed described in graphic 2, and its mode is to make 3-ketone group-propanoate ester derivatives and solution and the alkali such as the Et of the nitrogenize 4-acetylaminohydroxyphenylarsonic acid benzene sulfonyl that changes ₃The N reaction.With the subsequent disposal of carboxamide derivative and catalyzer such as four (acetoxy groups), two rhodiums (II) duohydrate, then for using triphenyl phosphine and iodine, in alkali such as Et ₃Cyclic action under N exists obtains indivedual ester derivatives.The ester functional group uses the saponification of currently known methods in this skill, for example with alkali, such as NaOH, in solvent or solvent mixture such as ethanol/water or THF, handle, obtain desired acid derivative.Indivedual 3-ketone group-propanoate ester derivatives are commercial get or known in this field.

Graphic 2: oxazoles synthesize (2)

Perhaps, the compound of structure 7, wherein R ²Expression hydrogen can be processed described in graphic 2b, and its mode is to make formula R ¹Solution of COOH acid derivative and isocyano-ritalin under alkali such as salt of wormwood sesquialter hydrate or DIPEA and DPPA existence, react in solvent such as DMF.The ester functional group uses the saponification of currently known methods in this skill, for example with alkali, such as NaOH, in solvent or solvent mixture such as ethanol/water or THF, handle, obtain indivedual acid derivatives.Indivedual acids R ¹COOH is commercial gets or known in this field.

Graphic 2b: oxazole synthesizes (3)

Perhaps, the compound of structure 7 can be processed described in graphic 3, and its mode is that 3-Phenserine verivate uses reagent, such as the dichloride thionyl, and in solvent such as MeOH, the esterification under about 0 ℃ of temperature then is and carboxylic acid derivative R ²-COOH uses standard conditions, such as HOBt, DCC, N-methylmorpholine, in solvent such as CH ₂Cl ₂In, coupling under about 0 ℃ temperature.

Alcohol is with oxidising agent, such as Dess-Martin crosses iodine alkane, in solvent such as CH ₂Cl ₂In oxygenizement, then use triphenyl phosphine and iodine, in alkali such as Et ₃There is cyclic action down in N, acquisition Ge other oxazole verivate.Desired acid derivative can be used the saponification of currently known methods in this skill and obtains by the ester functional group, for example with alkali, such as the LiOH aqueous solution, in solvent such as dioxy land surround, handle.

Graphic 3: oxazoles synthesize (4)

Perhaps, the compound of structure 7 can be by described in graphic 4, and use following order to process: a) the chlorination acyl is by suitable formula R ¹COOH acid is used DMF with chlorination oxalyl and catalysis, in solvent such as 1, and in the 2-ethylene dichloride, the formation of under the temperature of about room temperature, handling; B) formed chlorination acyl uses the isocyano-vinyl acetic monomer, in the alkali example in solvent such as THF

Graphic 4: oxazoles synthesize (5)

Embodiment

Experiment partly

Abbreviation (when in this paper and in preceding text expository writing, using)

The I chemistry

Generally, all temperature all with degree centigrade (℃) statement.Only if point out in addition, otherwise reaction is at room temperature carried out.

As the SCX material, use

SCX that derives from Silicycle.

As the DCC that polymer carried, use the PL-DCC that derives from Polymer Laboratories.

Analyzing thin layer chromatography (TLC) carries out with 0.2 millimeter plate: Merck, silica gel 60F ₂₅₄Preparation thin-layer chromatography (TLC) carries out with 0.2 or 0.5 millimeter plate: Merck, silica gel 60F ₂₅₄Detecting is with UV or with KMnO ₄(3 gram), K ₂CO ₃(20 gram), NaOH 5% (3 milliliters) and H ₂The solution of O (300 milliliters) carries out, and then heating.

Hurried formula tubing string chromatography (FC) uses silica gel 60Merck (0.063-0.200 millimeter) or Macherey-Nagel silica gel (0.063-0.200 millimeter) to carry out with filtration; With EA, heptane, CH ₂Cl ₂, CHCl ₃, MeOH or its mixture dissolve and leave.

The MPLC use derives from international sorbing agent technology

The hurried formula SI II of SPE tubing string carries out, with EA, Et ₂O, heptane, hexane, CH ₂Cl ₂, CHCl ₃, MeOH, NH ₄OH or its mixture dissolve and leave.

LC-MS-condition 01 when not indicating in addition (if): analyze: Thermo Finnigan MSQ Surveyor MS with Agilent 1100 binary pump and DAD.Tubing string: derive from 5 microns of the technological Zorbax SB-AQ of Agilent, 4.6 * 50 millimeters internal diameters.Eluent: A:H ₂O+0.04%TFA; B:AcCN; Gradient liquid: 5%B → 95%B went through 1 minute.Flow: 4.50 ml/min.Detecting: UV/Vis and/or ELSD and MS, t _RWith a minute expression.

LC-MS-condition 02 when not indicating in addition (if): analyze: Thermo Finnigan MSQ Plus MS with Agilent 1100 binary pump and DAD.Tubing string: derive from 5 microns of the technological Zorbax SB-AQ of Agilent, 4.6 * 50 millimeters internal diameters.Eluent: A:H ₂O+0.04%TFA; B:AcCN; Gradient liquid: 5%B → 95%B went through 1 minute.Flow: 4.50 ml/min.Detecting: UV/Vis and/or ELSD and MS, t _RWith a minute expression.

LC-MS-condition 05c when not indicating in addition (if): analyze: Dionex GHP 3200 binary pump, MS:Thermo MSQ Plus, DAD:Dionex PDA 3000, ELSD:Sedere Sedex 85.Tubing string: in Dionex TCC-3200 compartment through 1.8 microns of the thermoregulated Zorbax SB-AQ that derives from Agilent technology, 4.6 * 20 millimeters internal diameters.Eluent: A:H ₂O+0.04%TFA; B:AcCN.Method: gradient liquid: 5%B → 95%B, went through 1 minute.Flow: 4.5 ml/min.Detecting: UV/Vis and/or ELSD and MS, t _RWith a minute expression.

LC-MS-condition 06 when not indicating in addition (if): analyze: Dionex HPG-3000 binary pump, MS:Thermo MSQ MS, DAD:Dionex PDA 3000, ELSD:PolymerLab ELS 2100.Tubing string: in Dionex TCC-3000 compartment through 2.7 microns of the thermoregulated Ascentis C18 that derives from Sigma-Aldrich, 3 * 30 millimeters internal diameters.Eluent: A:H ₂O+0.05%TFA; B:AcCN.Method: gradient liquid: 5%B → 95%B, went through 2.40 minutes.Flow: 3.0 ml/min.Detecting: UV/Vis and/or ELSD and MS, t _RWith a minute expression.

LC-MS-condition 07 when not indicating in addition (if): analyze: DionexHGP-3200RS binary pump, MS:Thermo MSQ Plus, DAD:DionexDAD-3000RS, ELSD:Sedere Sedex 85.Tubing string: in Dionex TCC-3200 compartment through 3.5 microns of the Zorbax SB-AQ of the Agilent technology of deriving from of temperature adjustment (40 ℃), 4.6 * 50 millimeters internal diameters.Eluent: A:H ₂O+0.04%TFA; B:AcCN.Method: gradient liquid: 5%B → 95%B, went through 1 minute.Flow: 4.5 ml/min.Detecting: UV/Vis and/or ELSD and MS, t _RWith a minute expression.

LC-MS-condition 08 when not indicating in addition (if): analyze: Dionex HPG-3000 binary pump, MS:Thermo MSQ MS, DAD:Dionex PDA 3000, ELSD:PolymerLab ELS 2100.Tubing string: in Dionex TCC-3000 compartment through 2.5 microns of the XBridge C18 of temperature adjustment (50 ℃), 2.1 * 20 millimeters.Eluent: A:H ₂O+0.05%TFA; B:AcCN.Method: gradient liquid: 5%B → 95%B, went through 2.00 minutes.Flow: 1.4 ml/min.Detecting: UV/Vis and/or ELSD and MS, t _RWith a minute expression.

Preparation HPLC: derive from the X-Bridge C185 micron of Waters, 50 * 19 millimeters internal diameters.Eluent: A:H ₂O+0.5%NH ₄OH; B:AcCN; Gradient liquid: 10%B → 90%B went through 5 minutes.Flow: 40.0 ml/min.Detecting: UV/Vis and/or ELSD and MS, t _RWith a minute expression.

NMR:Bruker Avance 400 (400MHz); Varian Mercury 300 (300MHz); Chemical shift is represented with the ppm with respect to used solvent; Multiplicity: the s=singlet, the d=doublet, the t=triplet, the q=quartet, the p=quintet, the hex=sextet, the hept=septet, the m=multiplet, br=is broad, and coupling constant is represented with Hz.

Following embodiment explains the present invention, but does not limit its scope fully.

General procedure

General procedure A: acid amides coupling:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with acid (1.0 equivalent) at CH ₂Cl ₂In 0.2M solution handle with DMAP (0.25 equivalent), HOBt (1.2 equivalent), EDC (2.5 or 1.0 equivalent) and DIPEA (4.0 equivalent), and formed mixture was stirred under room temperature 30 minutes.Add aminotriazole derivatives (1.0 equivalent) at CH ₂Cl ₂In 0.2M solution, and with formed reaction mixture stirred overnight under room temperature.Add CH ₂Cl ₂, and with organic phase with water and brine wash.Make organic phase with Na ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent.Residue obtains desired compound by the purifying of FC or HPLC.

General procedure E: esterolysis:

With indivedual carboxylicesterss (1.0 equivalent) THF and corresponding alkyl alcohol thereof for example the 0.5M solution in 3: 1 mixtures of MeOH or EtOH handle with the 1M NaOH aqueous solution (2.0 equivalent).After stirring 3 hours, form white suspension, and under reduced pressure remove volatile organic content.Remaining mixture with water (half of 3: 1 mixture amounts of THF and MeOH) dilution, is cooled off with ice bath, and by adding 1M HCl acidified aqueous solution (pH=3-4).Filter this suspension-s, and with residue with cold water washing, after drying, obtain desired carboxylic acid derivative.

Synthesizing of general procedure F:2-acetylaminohydroxyphenylarsonic acid 3-ketone group-propanoate ester derivatives:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, make the 2.5M solution of indivedual 3-ketone group-propanoate ester derivatives (1.0 equivalent) in Glacial acetic acid min. 99.5 be cooled to 10 ℃, and under this temperature, add NaNO ₂(1.16 equivalent) 8.2M solution in water.After adding completion (15 minutes), make solution be warmed to room temperature, and stirred 2 hours.Then, solution is poured in the water (Glacial acetic acid min. 99.5 volume 5.3 times), and after several minutes, crystallization begins to occur.This suspension-s is cooled off with ice bath, and collect crystallization through filtering.With filter cake for several times with cold water washing; And remove water down by distilling with methylbenzene azeotropic in decompression; Obtain indivedual 2-oximinos-3-ketone group-propanoate ester derivatives, make (the indivedual 3-ketone group-propanoate ester derivatives for 1.0 mmoles are 0.66 milliliter) in its 1: 1.3 mixture that is dissolved in acetic anhydride and Glacial acetic acid min. 99.5.In this solution, add sodium-acetate (0.06 equivalent) and HgCl ₂(0.002 equivalent).Mixture was refluxed 1 hour, be cooled to room temperature then, and filter.Solid is washed with ether, reclaim organic filtrating, with water washing 3 times, and with 1M K ₂CO ₃Solution washing once.Make organic layer with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent.Make crude product pass through the FC purifying, and get desired 2-acetylaminohydroxyphenylarsonic acid 3-ketone group-propanoate ester derivatives.

General procedure G: cyclic action (1):

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, make the 1.6M solution of indivedual 2-acetylaminohydroxyphenylarsonic acid 3-ketone group-propanoate ester derivatives (1.0 equivalent) in chloroform in ice/NaCl bathes, be cooled to about 0 ℃.With SOCl ₂(1.4 equivalent) is added in stirred solution, and temperature is maintained at about under 0 ℃, goes through 30 minutes.Then, solution was stirred one hour down in refluxing.Add other 0.25 equivalent SOCl ₂, and reaction mixture was refluxed one hour again.With 1M K ₂CO ₃The aqueous solution makes excessive SOCl ₂Cancellation.With water layer with the ether extracted twice.With the organic phase that merges once, and with MgSO with water washing ₄Dehydrate, filter, and under reduced pressure remove solvent, and Yaoed De oxazole verivate, it can pass through the FC purifying.

General procedure H: cyclic action (2):

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with Et ₃N (4.1 equivalent) then is that indivedual 2-(carbonyl-amino)-3-ketone group-propanoate ester derivatives (1.0 equivalent) is at CH ₂Cl ₂In 0.1M solution be added into triphenyl phosphine (2.0 equivalent) and iodine (2.0 equivalent) at CH ₂Cl ₂In 0.2M solution in.Reaction mixture was stirred under room temperature 1.5 hours.Under reduced pressure remove solvent, and make residue pass through the FC purifying, and Yaoed De oxazole verivate.

General procedure I:N-inserts:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under; With diazo verivate (1.0 equivalent) 1; 0.5M solution in the 2-ethylene dichloride is added into carboxamide derivative (1.0 equivalent) and acetic acid rhodium (II) (four (acetoxy groups), two rhodiums (II) duohydrate; 0.05, in the reflux solution in the 2-ethylene dichloride (3 milliliters of the carboxamide derivatives of every mmole), went through 1.5 hours equivalent) 1.Then, reaction mixture was stirred 1.5 hours down in refluxing.Under reduced pressure remove solvent, and make residue pass through the FC purifying, and get desired 2-(carbonyl-amino)-3-ketone group-propanoate ester derivatives.

General procedure J: diazotization:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with the 0.17M solution of 3-ketone group-propanoate ester derivatives (1.0 equivalent) in AcCN, under 0 ℃, with the nitrogenize 4-P-acetamido benzene sulfonyl (1.0 equivalent) that changes,

Then with Et ₃N (3.0 equivalent) handles.Reaction mixture was stirred under room temperature 1 hour.Under reduced pressure remove solvent, residue is developed in ether-sherwood oil, and filter.Under reduced pressure remove solvent, and make residue pass through the FC purifying, and get desired diazo verivate.

General procedure K:Claisen condensation:

A) in be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, 1, the 1.3M solution in the 2-ethylene dichloride under room temperature, with several DMF, is then handled with chlorination oxalyl (1.3 equivalent) with acid derivative (1.0 equivalent).Reaction mixture was at room temperature stirred 3 hours, then following 20 minutes in 80 ℃.Under reduced pressure remove solvent.

B) in be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with the 0.83M solution of potassium monoethyl malonate (2 equivalent) in acetonitrile, under 10 ℃, handle, and this suspension-s was stirred 30 minutes down in 10 ℃ with magnesium chloride (2.5 equivalent), and at room temperature 3 hours.Make reaction mixture be cooled to 0 ℃, and with chlorination acyl solution made under A, then with Et ₃N (2 equivalent) dropwise handles, and goes through 15 minutes.Formed suspension-s was at room temperature stirred 20 hours.Move down in decompression and to desolventize, and make residue with the toluene stripping.Residue is dissolved in the toluene (1.5 milliliters of the potassium monoethyl malonates of every mmole), and under 10 ℃, handles with 4M HCl with the toluene same amount.With organic layer with 4M HCl, water washing twice, with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent.Make residue pass through the FC purifying, and get desired verivate.

General procedure M: cyclic action (3):

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under; With acid (1.0 equivalent) 0.5M solution in DMF; Under room temperature, with salt of wormwood sesquialter hydrate, perhaps DIPEA (from 1.2 equivalent to 1.5 equivalents); Under room temperature, stirred 5 minutes then with the 2.0M solution-treated of isocyano-ritalin (from 1.5 equivalent to 3.2 equivalents) in DMF, and with mixture.Make reaction mixture be cooled to 0 ℃, and with the 0.67M solution-treated of DPPA (1.1 equivalent) in DMF.Formed suspension-s was stirred 2 hours down in 0 ℃, and at room temperature 15 hours.Then, it is poured over EA

General procedure N: cyclic action (4):

A) in be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, 1, the 1.0M solution in the 2-ethylene dichloride under room temperature, with several DMF, is then handled with chlorination oxalyl (1.3 equivalent) with acid derivative (1.0 equivalent).Reaction mixture was at room temperature stirred 3 hours, then following 20 minutes in 80 ℃.Under reduced pressure remove solvent.

B) in be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with the 0.7M solution of isocyano-vinyl acetic monomer (1 equivalent) in THF with DMAP (0.1 equivalent) and Et ₃N (2.2 equivalent) handles, and reaction mixture is heated to 60 ℃, dropwise be added on then chlorination acyl made under the A THF solution (for isocyano-vinyl acetic monomer volume that solution uses 1/5), then mixture is descended stirring 1.5 hours in 75 ℃.Add 25%HCl, then be TBDME.With organic layer with saturated NaHCO ₃Solution washing is with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent.Make residue pass through the FC purifying, and get desired verivate.

General procedure O: oxazole open loop and N-acetylizing:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) descend ， Jiang the 0.43M solution of oxazole verivate (1.0 equivalent) in EtOH, under 0 ℃, handle with ethanoyl chlorine (9 equivalent), keep temperature to be lower than 10 ℃ simultaneously.

Then, with reaction mixture 50 ℃ of following stirred overnight.Move down in decompression and to desolventize, and with residue under 0 ℃, with the 1.3M solution-treated of sodium-acetate (2 equivalent) in water.Then, dropwise add acid anhydride (2 equivalent).After 30 minutes, add TBDME, and with organic phase with water washing, with Na ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent.Make residue pass through the FC purifying, and get desired verivate.

General procedure P: cyclic action (5):

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with the 0.65M solution of acid amides in vitriol oil stirred overnight under room temperature.Then, reaction mixture is poured onto on ice, and with 4-methyl-propione extracted several times.The organic phase that makes merging is with Na ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent.Can make residue pass through the FC purifying, and get desired verivate.

Synthesizing of general procedure Q:2-acetylaminohydroxyphenylarsonic acid 3-ketone group-propanoate ester derivatives:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, make the 2.5M solution of indivedual 3-ketone group-propanoate ester derivatives (1.0 equivalent) in Glacial acetic acid min. 99.5 be cooled to 10 ℃, and under this temperature, add NaNO ₂(1.16 equivalent) 8.2M solution in water.After adding completion (15 minutes), make solution be warmed to room temperature, and stirred 2 hours.Then, solution is poured in the water (Glacial acetic acid min. 99.5 volume 5.3 times), and after several minutes, crystallization begins to occur.This suspension-s is cooled off with ice bath, and collect crystallization through filtering.With filter cake for several times with cold water washing; And remove water down by distilling with methylbenzene azeotropic in decompression; Obtain indivedual 2-oximinos-3-ketone group-propanoate ester derivatives, it is dissolved in acetic anhydride (3.0 equivalent) and the acetic acid (the indivedual 2-oximinos of every gram-3-ketone group-propanoate ester derivatives 1 milliliter).In this solution, add sodium-acetate (0.06 equivalent) and ZnCl ₂(0.002 equivalent).Then, mixture is handled with Zn powder (3.0 equivalent) gradation, gone through 15 minutes.Made reaction mixture refluxed 0.5 hour, and be cooled to room temperature then, and filter.Solid is washed with ether, reclaim organic filtrating, with water washing 3 times, and with 1M K ₂CO ₃Solution washing once.Make organic layer with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get desired 2-acetylaminohydroxyphenylarsonic acid 3-ketone group-propanoate ester derivatives.

General procedure Z2: acid amides coupling:

In the little glass bottle that contains the acid (0.15 mmole) that is dissolved among the DMF/DCM 1/1 (500 microlitre), insert 0.5 normal 1M HOAT (50 microlitres in DMF; 0.05 mmole) with 2 equivalent Si-carbodiimide (Si-DCC), 1.08 mmole/grams.Then, interpolation has been dissolved in the amine (1 equivalent) among the DMF/DCM 1/1 (200 microlitre).Mixture is at room temperature stirred a night.Add PL-DETA resin 2 equivalents in each little glass bottle, and mixture was at room temperature stirred 22 hours.2 milliliters of DCM/DMF 1/1 are added into reaction

Synthesizing of intermediate

4-bromo-thiazole-2-carboxylic formaldehyde:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with commercial get 2,4-two bromo-thiazoles (3.50 gram, 14.41 mmoles) are at anhydrous Et ₂Solution among the O (120 milliliters) under-78 ℃, is handled with n-BuLi (5.9 milliliters, the 2.5M solution in hexane, 14.72 mmoles).Reaction mixture was stirred 30 minutes under this temperature.Then, add N, dinethylformamide (1.35 milliliters, 14.47 mmoles), and make mixture be warmed to room temperature, during going through 1 hour.By adding saturated NH ₄The Cl aqueous solution (50 milliliters) makes the reaction cancellation.Separate liquid layer, and with water layer with Et ₂O (3 * 50 milliliters) extraction.The organic collection liquid that makes merging is with Na ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent.(10: 1-＞3: 1 heptane-EA), obtain title compound is faint yellow solid to the purifying of residue through FC.TLC: rf (1: 1 heptane-EA)=0.21.LC-MS-condition 02:t _R=0.81 minute.

(4-bromo-thiazol-2-yl)-methyl alcohol:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, 4-bromo-thiazole-2-carboxylic formaldehyde (1.68 grams, 8.75 mmoles) is dissolved among the MeOH (10 milliliters).Under 0 ℃, NaBH is added in gradation ₄(428 milligrams, 10.86 mmoles), and reaction mixture stirred under room temperature 1 hour.Add water (10 milliliters), and mixture is extracted with EA (3 * 20 milliliters).The organic collection liquid that makes merging is with Na ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent.(6: 1-＞2: 1 heptane-EA), obtain title compound is faint yellow solid to the purifying of residue through FC.TLC: rf (1: 1 heptane-EA)=0.31.LC-MS-condition 02:t _R=0.62 minute [M+H] ⁺194.31.

4-bromo-2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-thiazole:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, make (4-bromo-thiazol-2-yl)-methyl alcohol (1.37 grams, 7.06 mmoles) be dissolved in anhydrous CH ₂Cl ₂In (21 milliliters).Under 0 ℃, add chlorination tertiary butyl dimethylsilane (1.17 grams, 7.77 mmoles), then be imidazoles (985 milligrams, 14.47 mmoles).Reaction mixture was stirred under room temperature 2 hours.Add 10%K ₂CO ₃The aqueous solution (10 milliliters) separates liquid layer, and with water layer with CH ₂Cl ₂(2 * 20 milliliters) extraction.The organic collection liquid that makes merging is with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get title compound, be water white oil.TLC: rf (1: 1 heptane-EA)=0.80.

1-[2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-thiazole-4-yl]-ethyl ketone:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, in 4-bromo-2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-thiazole (1.94 gram, 6.29 mmoles) at anhydrous Et ₂In the solution among the O (50 milliliters), add n-BuLi (2.76 milliliters, the 2.5M solution in hexane, 6.92 mmoles) down at-78 ℃.Then, reaction mixture was stirred 30 minutes down in-78 ℃, then dropwise add DMAC N,N (1.17 milliliters, 12.58 mmoles).Make reaction mixture be warmed to room temperature, during going through 1 hour, and under this temperature, stirred 20 minutes.Add saturated NH ₄The Cl aqueous solution (20 milliliters) separates liquid layer, and with water layer with Et ₂O (3 * 30 milliliters) extraction.The organic collection liquid that makes merging is with Na ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent.(20: 1-＞5: 1 heptane-EA), obtain title compound is yellow solid to the purifying of residue through FC.TLC: rf (1: 1 heptane-EA)=0.51.LC-MS-condition 02:t _R=1.11 minutes; [M+H] ⁺=272.39.

2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-4-(2-methyl-[1,3] dioxolane-2-yl)-thiazole:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, the solution of 1-[2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-thiazole-4-yl]-ethyl ketone (1.77 grams, 6.52 mmoles) in terepthaloyl moietie (7 milliliters) is followed with LiBF with trimethyl orthoformate (1.46 milliliters, 13.29 mmoles) ₄(125 milligrams, 1.30 mmoles) are handled.Reaction mixture was heated 4 hours down at 95 ℃.Add saturated Na ₂CO ₃The aqueous solution (5 milliliters), and with mixture with Et ₂O (2 * 20 milliliters) extraction.Make organic collection liquid with Na ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent.The purifying of residue through FC (20: in 1-＞3: 1 alkane heptan-EA), obtain title compound, be brown oil.TLC: rf (1: 1 heptane-EA)=0.56.LC-MS-condition 02:t _R=1.11 minutes; [M+H] ⁺=316.36.

[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl]-methyl alcohol:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-4-(2-methyl-[1,3] dioxolane-2-yl)-thiazole (1.30 grams; 4.12 the solution in anhydrous THF (10 milliliters) mmole) is under 0 ℃, with (6.2 milliliters of TBAF; 1M solution in THF, 6.20 mmoles) handle.Reaction mixture was stirred 5 minutes down in 0 ℃, and at room temperature 1 hour 30 minutes.Then, mixture with EA (10 milliliters) dilution, is washed with salt solution (3 * 10 milliliters), with MgSO ₄Dehydrate, filter, and under reduced pressure concentrate.(5: 1-＞1: 3 heptane-EA), obtain title compound is yellow oil to the purifying of residue through FC.TLC: rf (1: 2 heptane-EA)=0.20.LC-MS-condition 02:t _R=0.59 minute; [M+H] ⁺=202.48.

2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-4-nitro-2H-[1,2,3] triazole:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with [4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl]-methyl alcohol (18.460 gram, 91.73 mmoles) at anhydrous CH ₂Cl ₂Solution in (300 milliliters) is under 0 ℃, with Et ₃N (16.59 milliliters, 118.62 mmoles) then handles with Ms-Cl (9.17 milliliters, 115.83 mmoles) with DMAP (1.132 grams, 9.17 mmoles).After stirring 1 hour under 0 ℃, make the reaction cancellation with water (80 milliliters).Separate liquid layer, and with water layer with CH ₂Cl ₂(3 *) extraction.Make organic layer with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get thick methanesulfonic 4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl esters, be brown oil.With (2.756 grams of this crude material of part among the DMF (20 milliliters); 9.87 mmole) be added into through 4-nitro-2H-[1,2 of 30 minutes of DIPEA (3.18 milliliters, 18.59 mmoles) pre-treatment; 3] triazole (10.60 grams; 10% solution in acetone, 9.29 mmoles) in the solution in DMF (20 milliliters), and with reaction mixture in 50 ℃ of following stirred overnight.Add water (25 milliliters), then be EA (50 milliliters).With EA (50 milliliters) extraction, and the organic collection liquid that makes merging is with Na with water layer ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent.(1: 2 heptane-EA), obtain title compound is yellow solid: TLC: rf (1: 2 heptane-EA)=0.52 to the purifying of residue through FC.LC-MS-condition 02:t _R=0.88 minute, [M+H] ⁺=297.84.

1-[2-(4-nitro-[1,2,3] triazole-2-ylmethyl)-thiazole-4-yl]-ethyl ketone:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under; With 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-4-nitro-2H-[1,2; 3] triazole (2.360 grams; 7.94 mmole) solution in THF (40.0 milliliters) is handled with 1N HCl (21.4 milliliters, 21.4 mmoles), and with reaction mixture stirred overnight under room temperature.Make the reaction mixture neutralization with 1N NaOH.With EA (20 milliliters) extracted twice, and the organic collection liquid that makes merging is with MgSO with water layer ₄Dehydrate, filter, and under reduced pressure remove solvent.(6: 4 heptane-EA), obtain title compound are yellow solid: TLC: rf (6: 4 heptane-EA)=0.29 to the purifying of residue through FC.LC-MS-condition 02:t _R=0.81 minute, [M+H] ⁺=254.35.

2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-4-nitro-2H-[1,2,3] triazole:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, 1-[2-(4-nitro-[1,2,3] triazole-2-ylmethyl)-thiazole-4-yl]-ethyl ketone (1.000 grams, 3.95 mmoles) with Deoxo-Fluor (17.47 grams, 50% solution in toluene, 39.49 mmoles), is then handled with EtOH (0.2 milliliter).With reaction mixture in 60 ℃ of following stirred overnight.Reaction mixture is poured over saturated Na ₂CO ₃On the aqueous solution (60 milliliters).With EA (60 milliliters) extracted twice, and organic collection liquid that will merge is with saturated Na with water layer ₂CO ₃The aqueous solution (60 milliliters), water (60 milliliters) washing are with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent.(7: 3 heptane-EA), obtain title compound are orange solids: TLC: rf (7: 3 heptane-EA)=0.32 to the purifying of residue through FC.LC-MS-condition 02:t _R=0.96 minute.

2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-4-nitro-2H-[1,2,3] triazole (491 milligrams, 1.78 mmoles), iron powder (302 milligrams, 5.35 mmoles) and NH ₄The mixture of Cl (482 milligrams, 8.92 mmoles) in the mixture of EtOH (8.0 milliliters) and water (4.0 milliliters) stirred 20 minutes down in 85 ℃.The filtered while hot reaction mixture, and under reduced pressure concentrate.Add CH ₂Cl ₂(20 milliliters) then are water (20 milliliters).With water layer with CH ₂Cl ₂(2 * 10 milliliters) extraction, and the organic collection liquid that makes merging is with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get title compound, be yellow oil.LC-MS-condition 02:t _R=0.76 minute; [M+H] ⁺=246.16.

(E)-2-styryl-oxazoles-4-carboxylic acid, ethyl ester:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 3-phenyl-acrylic amide (10.31 grams, 67.95 mmoles) and NaHCO ₃(28.47 grams, 339.73 mmoles) suspension-s in THF (260 milliliters) is handled with 3-bromo-2-ketone group-ethyl propionate (13.04 milliliters, 88.33 mmoles), and reaction mixture was heated 15 hours down in refluxing.Add 3-bromo-2-ketone group-ethyl propionate (13.04 milliliters, 88.33 mmoles) again, and reaction mixture was stirred 15 hours down in refluxing.Then, reaction mixture is filtered on zeyssatite, and the vapourisation under reduced pressure solvent.Residue is dissolved among the THF (30 milliliters), and under 0 ℃, dropwise handles with trifluoro-acetic anhydride (30.0 milliliters, 215.83 mmoles).Then, with reaction mixture stirred overnight under room temperature.Add saturated Na ₂CO ₃The aqueous solution, and with mixture with EA (3 * 150 milliliters) extraction, with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent.Residue is through the purifying (1: the 9EA-heptane), obtain title compound, be yellow solid of FC.TLC: rf (1: the 9EA-heptane)=0.1.LC-MS-condition 02:t _R=1.01 minutes; [M+H] ⁺=244.48.

2-Jia Xian Ji oxazole-4-carboxylic acid, ethyl ester:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with NaIO ₄(3.21 gram, 15.00 mmoles) solution in water (26.0) milliliter slowly be added into silica gel (15.0 gram) in acetone (60.0 milliliters) in high degree of agitation suspension-s.Then, mixture is concentrated down in decompression, and with blocks of solid at CH ₂Cl ₂In be made into slurries, and vapourisation under reduced pressure solvent.Add CH ₂Cl ₂(40.0 milliliters), and with reaction mixture under room temperature with (E)-2-styryl-oxazoles-4-carboxylic acid, ethyl ester (1.22 gram, 5.00 mmoles) and RuCl ₃Hydrate (82 milligrams, 0.15 mmole) is handled.With reaction mixture at room temperature, in dark, stirred 30 minutes, filter, and under reduced pressure concentrate.(1: 9 to 1: the 2EA-heptane), obtain title compound, be yellow solid for the purifying of residue through FC.TLC: rf (3: the 2EA-heptane)=0.21.LC-MS-condition 02:t _R=0.51 minute; [M+H ₂O+H] ⁺=188.50.

2-methylol-oxazoles-4-carboxylic acid, ethyl ester:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, 2-Jia Xian Ji oxazole-4-carboxylic acid, ethyl ester (272 milligrams, 1.61 mmoles) is dissolved among the EtOH (5.0 milliliters).Under 0 ℃, NaBH is added in gradation ₄(112 milligrams, 2.84 mmoles), and reaction mixture stirred 1 hour down in 0 ℃.Add saturated NH ₄The Cl aqueous solution, and mixture extracted with EA (5 * 10 milliliters).The organic collection liquid that makes merging is with Na ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get title compound, be yellow oil.TLC∶rf(EA)＝0.50。LC-MS-condition 02:t _R=0.58 minute; [M+H] ⁺=172.03.

2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-oxazoles-4-carboxylic acid, ethyl ester:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, make 2-methylol-oxazoles-4-carboxylic acid, ethyl ester (275 milligrams, 1.61 mmoles) be dissolved in anhydrous CH ₂Cl ₂In (5.0 milliliters).At room temperature, add chlorination tertiary butyl dimethylsilane (510 milligrams, 3.22 mmoles), then be imidazoles (221 milligrams, 3.22 mmoles).Reaction mixture was stirred under room temperature 30 minutes.Add water, separate liquid layer, and make organic layer with Na ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent.(1: 20 to 1: the 9EA-heptane), obtain title compound, be water white oil for the purifying of residue through FC.TLC: rf (9: 1 heptane-EA)=0.15.LC-MS-condition 02:t _R=1.10 minutes; [M+H] ⁺=286.38.

2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-oxazoles-4-carboxylic formaldehyde:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-oxazoles-4-carboxylic acid, ethyl ester (283 milligrams, 0.99 mmole) at CH ₂Cl ₂Solution in (5.0 milliliters) under-78 ℃, is handled with DiBAL (1.85 milliliters, the 1M solution in toluene, 1.85 mmoles), and reaction mixture was stirred 1 hour down at-78 ℃.Add MeOH (70 microlitre) and H ₂O (100 microlitre), and make reaction mixture be warmed to room temperature.Filter reaction mixture, and under reduced pressure remove solvent, and get title compound, be water white oil.TLC: rf (1: 1 heptane-EA)=0.61.LC-MS-condition 02:t _R=1.03 minutes; [M+H ₂O+H] ⁺=260.50.

1-[2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-oxazoles-4-yl]-ethanol:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-oxazoles-4-carboxylic formaldehyde (223 milligrams, 0.92 mmole) at CH ₂Cl ₂Solution in (8.0 milliliters) under 0 ℃, is handled with trimethylaluminium (2.50 milliliters, the 2M solution in toluene, 5.00 mmoles).Then, reaction mixture was stirred 45 minutes down at 0 ℃.Then, add saturated NH ₄The Cl aqueous solution, and with water layer with CH ₂Cl ₂Extracted twice, and with twice of EA.The organic collection liquid that makes merging is with Na ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get title compound, be water white oil.TLC: rf (1: 1 heptane-EA)=0.32.LC-MS-condition 02:t _R=0.97 minute, [M+H] ⁺258.30.

1-[2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-oxazoles-4-yl]-ethyl ketone:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 1-[2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-oxazoles-4-the yl]-solution of ethanol (193 milligrams, 0.75 mmole) in AcCN (5.0 milliliters), under room temperature, with MnO ₂(362 milligrams, 3.75 mmoles) are handled.Reaction mixture was at room temperature stirred 16 hours, pass through diatomite filtration then.Move down in decompression and to desolventize, and title compound, be white solid.TLC: rf (1: 1 heptane-EA)=0.69.LC-MS-condition 02:t _R=1.04 minutes, [M+H] ⁺255.84.

1-(2-methylol-oxazoles-4-yl)-ethyl ketone:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 1-[2-(tertiary butyl-dimethyl--silanyloxy ylmethyl)-oxazoles-4-the yl]-solution of ethyl ketone (192 milligrams, 0.75 mmole) in anhydrous THF (5.0 milliliters); Under room temperature; Handle with TBAF (1.1 milliliters, the 1M solution in THF, 1.10 mmoles).Reaction mixture was stirred under room temperature 1.5 hours.Then, mixture with EA (10 milliliters) dilution, is washed with salt solution (3 * 10 milliliters), with Na ₂SO ₄Dehydrate, filter, and under reduced pressure concentrate.(1: 1 to 2: the 1EA-heptane), obtain title compound, be faint yellow solid for the purifying of residue through FC.TLC∶rf(EA)＝0.37。LC-MS-condition 02:t _R=0.34 minute, [M+H] ⁺=142.46.

Methanesulfonic 4-ethanoyl-oxazoles-2-base methyl esters:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 1-(2-methylol-oxazoles-4-yl)-ethyl ketone (75 milligrams, 0.53 mmole) at anhydrous CH ₂Cl ₂Solution in (5.0 milliliters) is under 0 ℃, with Et ₃N (0.10 milliliter, 0.71 mmole) then handles with DMAP (6 milligrams, 0.05 mmole) and Ms-Cl (0.05 milliliter, 0.66 mmole).After stirring 30 minutes under 0 ℃, make the reaction mixture cancellation with water (10 milliliters), with CH ₂Cl ₂(10 milliliters) extraction, and the organic collection liquid that makes merging is with Na ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get title compound, be yellow oil.TLC∶rf(EA)＝0.63。LC-MS-condition 02:t _R=0.64 minute; [M+H] ⁺=220.22.

1-[2-(4-nitro-[1,2,3] triazole-2-ylmethyl)-oxazoles-4-yl]-ethyl ketone:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under; The methanesulfonic 4-ethanoyl-oxazoles-solution of 2-base methyl esters (116 milligrams, 0.53 mmole) in DMF (3.0 milliliters) is added into through 4-nitro-2H-[1 of 30 minutes of DIPEA (0.20 milliliter, 1.17 mmoles) pre-treatment; 2; 3] in the solution of triazole (62 milligrams, 0.53 mmole) in DMF (2.0 milliliters), and reaction mixture stirred 20 hours down in 50 ℃.Add water (10 milliliters), then be EA (10 milliliters).With EA (10 milliliters) extraction, and the organic collection liquid that makes merging is with NaSO with water layer ₄Dehydrate, filter, and under reduced pressure remove solvent.(3: 1 to 1: 1 heptane-EA), obtain title compound are yellow solid to the purifying of residue through FC.TLC: rf (1: 2 heptane-EA)=0.49.LC-MS-condition 01:t _R=0.76 minute.

2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-4-nitro-2H-[1,2,3] triazole:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, 1-[2-(4-nitro-[1,2,3] triazole-2-ylmethyl)-oxazoles-4-yl]-ethyl ketone (170 milligrams, 0.72 mmole) with Deoxo-Fluor (3.17 grams, 50% solution in toluene, 7.17 mmoles), is then handled with EtOH (0.2 milliliter).Reaction mixture was stirred 16 hours.Reaction mixture is poured over saturated Na ₂CO ₃On the aqueous solution (5 milliliters).With methylene dichloride (6 milliliters) extracted twice, and organic collection liquid that will merge is with saturated Na with water layer ₂CO ₃The aqueous solution (6 milliliters), water (6 milliliters) washing are with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent.The purifying of residue through FC (1000: 12.2: 1 to 1000: 100: 8CH ₂Cl ₂-MeOH-NH ₄OH), obtain title compound, be yellow oil: TLC: rf (1: 2 heptane-EA)=0.58.LC-MS-condition 05c:t _R=0.45 minute.

2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-4-nitro-2H-[1,2,3] triazole (130 milligrams, 0.50 mmole), iron powder (85 milligrams, 1.41 mmoles) and NH ₄The mixture of Cl (136 milligrams, 2.51 mmoles) in the mixture of EtOH (2.0 milliliters) and water (1.0 milliliters) stirred 60 minutes down in 70 ℃.The filtered while hot reaction mixture, and under reduced pressure concentrate.Add CH ₂Cl ₂(10 milliliters) then are water (10 milliliters).With water layer with CH ₂Cl ₂(2 * 10 milliliters) extraction, and the organic collection liquid that makes merging is with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get title compound, be yellow oil.LC-MS-condition 05c:t _R=0.47 minute.

1-(5-methylol-furans-2-yl)-ethyl ketone:

In in flame-dried round-bottomed flask, at rare gas element (N ₂) under, in 5-methylol-2-Furan Aldehydes (100 gram, 0.79 mole) and toluene-4-sulfonic acid pyridinium salt (10 grams, 0.04 mole) at CH ₂Cl ₂In the mixture in (1 liter), add 3,4-dihydro-2H-pyrans (150 milliliters, 1.62 moles) keeps internal temperature to be lower than 28 ℃ (water-baths) simultaneously.Reaction mixture was stirred under room temperature 5 hours.Add water (1 liter), separate liquid layer, and with organic layer with water (500 milliliters) washing, and be evaporated to dry, and rough 5-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-furans-2-carboxylic formaldehyde, be yellow oil (171 grams, quantitatively).

Make rough 5-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-furans-2-carboxylic formaldehyde (171 gram) be dissolved among the THF (1 liter), and be cooled to 1 ℃.Then, and the interpolation methylmagnesium-chloride (3M, in THF, 325 milliliters, 0.97 mole), keep internal temperature to be lower than 5 ℃ simultaneously.After adding, reaction mixture was at room temperature stirred 1 hour.Add water (1 liter), TBME (1 liter) and 40% aqueous citric acid solution (200 milliliters); Separate liquid layer; And with organic layer with water (500 milliliters) washing, and be evaporated to dryly, obtain the rough 1-of 174 grams [5-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-furans-2-yl]-ethanol (95% productive rate).Making partly, crude material (96 grams, 0.43 mole) is dissolved in CH ₂Cl ₂In (1 liter), and at room temperature with MnO ₂(371 grams, 4.26 moles) are handled.Reaction mixture is heated to 45 ℃, and under this temperature, stirred 24 hours.Then, mixture is filtered on zeyssatite, and with filter cake with CH ₂Cl ₂Washing.Evaporated filtrate is extremely dry, and gets rough 1-[5-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-furans-2-yl]-ethyl ketone (89 grams, 93%), is yellow oil.

Make rough 1-[5-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-furans-2-yl]-ethyl ketone (89 grams, 0.40 mole) be dissolved among the MeOH (500 milliliters), and at room temperature handle with Amberlyst 15 (15 gram).Reaction mixture was stirred 1 hour down at 35 ℃, be cooled to room temperature, and on zeyssatite, filter.Add Et ₃N (1 milliliter), and it is dry that mixture is evaporated to.Make residue with the methylcyclohexane stripping, and obtain 1-(5-methylol-furans-2-yl)-ethyl ketone (55 grams, 99%), be yellow oil, it solidifies when leaving standstill.

1-[5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-furans-2-yl]-ethyl ketone:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 1-(5-methylol-furans-2-yl)-ethyl ketone (2.00 gram, 14.27 mmoles) at anhydrous CH ₂Cl ₂Solution in (29 milliliters) is under 0 ℃, with Et ₃N (2.58 milliliters, 18.55 mmoles) then handles with DMAP (178 milligrams, 1.43 mmoles) and Ms-Cl (1.33 milliliters, 17.13 mmoles).After at room temperature stirring 3 hours, make the reaction cancellation with water.Separate liquid layer, and with water layer with CH ₂Cl ₂(3 *) extraction.Make organic layer with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get 3.93 gram (quantitatively) rough 1-(5-chloro methyl-furans-2-yl)-ethyl ketones, be brown oil.With (1.718 grams of this crude material of part among the DMF (10.3 milliliters); 10.83 mmole) be added into through 4-nitro-2H-[1,2 of 30 minutes of DIPEA (3.09 milliliters, 18.06 mmoles) pre-treatment; 3] triazole (10.30 grams; 10% solution in acetone, 9.03 mmoles) in the solution in DMF (10.3 milliliters), and with reaction mixture in 50 ℃ of following stirred overnight.Add water (32 milliliters), then be EA (65 milliliters).With EA (65 milliliters) extraction, and the organic collection liquid that makes merging is with Na with water layer ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent.(2: 1 heptane-EA), obtain title compound are yellow solid: TLC: rf (2: 1 heptane-EA)=0.20 to the purifying of residue through FC.LC-MS-condition 02:t _R=0.85 minute, [M+H] ⁺=237.46.

2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-4-nitro-2H-[1,2,3] triazole:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, 1-[5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-furans-2-yl]-ethyl ketone (1.000 grams, 4.23 mmoles) with Deoxo-Fluor (18.73 grams, 50% solution in toluene, 42.34 mmoles), is then handled with EtOH (0.2 milliliter).Reaction mixture was stirred 2 days.Reaction mixture is poured over saturated Na ₂CO ₃On the aqueous solution (50 milliliters).With methylene dichloride (60 milliliters) extracted twice, and organic collection liquid that will merge is with saturated Na with water layer ₂CO ₃The aqueous solution (60 milliliters), water (60 milliliters) washing are with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent.(7: 3 heptane-EA), obtain title compound are orange solids: TLC: rf (7: 3 heptane-EA)=0.42.LC-MS-condition 02:t to the purifying of residue through FC _R=1.00 minutes.

2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine: [0165] in be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-4-nitro-2H-[1,2,3] triazole (471 milligrams, 1.82 mmoles), iron powder (309 milligrams, 5.47 mmoles) and NH ₄The mixture of Cl (493 milligrams, 9.12 mmoles) in the mixture of EtOH (7.0 milliliters) and water (3.5 milliliters) stirred 20 minutes down in 85 ℃.The filtered while hot reaction mixture, and under reduced pressure concentrate.Add CH ₂Cl ₂(10 milliliters) then are water (10 milliliters).With water layer with CH ₂Cl ₂(2 * 10 milliliters) extraction, and the organic collection liquid that makes merging is with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get title compound, be yellow oil.LC-MS-condition 02:t _R=0.82 minute; [M+H+AcCN] ⁺=270.24.

(E)-2-methyl-3-Phenyl Acrylamide:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with (E)-2-methyl-3-phenylacrylic acid (19.0 grams, 116 mmoles) and Et ₃The solution of N (17.1 milliliters, 122 mmoles) in THF (500 milliliters) under 0 ℃, is handled with Vinyl chloroformate (11.4 milliliters, 117 mmoles), and reaction mixture was stirred 15 minutes down at 0 ℃.Then, add NH ₄The solution of OH (250 milliliter of 25% aqueous solution) in THF (150 milliliters), and reaction mixture stirred under room temperature 90 minutes.With water layer with CH ₂Cl ₂Extracted twice, and organic collection liquid that will merge is with water washing, with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get title compound, be white solid.TLC∶rf(1000∶50∶4CH ₂Cl ₂-MeOH-NH ₄OH)＝0.25。

(E)-2-(1-phenyl third-1-alkene-2-base) oxazole-4-carboxylic acid, ethyl ester:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with (E)-2-methyl-3-Phenyl Acrylamide (29.4 grams, 182 mmoles) and NaHCO ₃(68.72 grams, 820 mmoles) suspension-s in THF (500 milliliters) is handled with 3-bromo-2-ketone group-ethyl propionate (45.74 milliliters, 309 mmoles), and reaction mixture was heated 20 hours down in refluxing.Add 3-bromo-2-ketone group-ethyl propionate (10.0 milliliters, 68 mmoles) again, and reaction mixture was stirred 10 hours down in refluxing.Then, reaction mixture is filtered on zeyssatite, and the vapourisation under reduced pressure solvent.Residue is dissolved among the THF (500 milliliters), and under 0 ℃, dropwise handles with trifluoro-acetic anhydride (78.0 milliliters, 555 mmoles).Then, with reaction mixture stirred overnight under room temperature.Add saturated Na ₂CO ₃The aqueous solution (250 milliliters), and with mixture with EA (4 * 250 milliliters) extraction, with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent.Residue is through the purifying (0: 1 → 1: the 9EA-heptane), obtain title compound, be brown oil of FC.TLC: rf (1: the 9EA-heptane)=0.13.

2-Yi Xian Ji oxazole-4-carboxylic acid, ethyl ester:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with NaIO ₄(23 gram, 108 mmoles) solution in water (150) milliliter slowly be added into silica gel (110 gram) in acetone (500 milliliters) in high degree of agitation suspension-s.Then, mixture is concentrated down in decompression, and with blocks of solid at CH ₂Cl ₂In be made into slurries, and vapourisation under reduced pressure solvent.Add CH ₂Cl ₂(500 milliliters), and with reaction mixture under room temperature with (E)-2-(1-phenyl third-1-alkene-2-base) oxazole-4-carboxylic acid, ethyl ester (8.3 grams, 32.5 mmoles) and RuCl ₃Hydrate (550 milligrams, 1.0 mmoles) is handled.Reaction mixture was at room temperature stirred 60 minutes in dark, filter, and under reduced pressure concentrate.Residue is through purifying (1: 0 → 1: 5 sherwood oil: Et of FC ₂O), obtain title compound, be yellow solid.TLC: rf (1: the 1EA-heptane)=0.52.

2-(1,1-two fluoro ethyls) oxazole-4-carboxylic acid, ethyl ester:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, 2-Yi Xian Ji oxazole-4-carboxylic acid, ethyl ester (1.15 grams, 6.28 mmoles) with two (2-methoxy ethyl) amino sulfur trifluoride (7.31 grams, 31.39 mmoles), is then handled with EtOH (0.2 milliliter).With reaction mixture in 60 ℃ of following stirred overnight.Reaction mixture is poured over saturated Na ₂CO ₃On the aqueous solution (25 milliliters).With the EA extracted twice, and organic collection liquid that will merge is with saturated Na with water layer ₂CO ₃The aqueous solution (25 milliliters), water (25 milliliters) washing are with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent.(5: 1 → 1: 1 heptane-EA), obtain title compound is yellow solid: TLC: rf (1: 2 heptane-EA)=0.8 to the purifying of residue through FC.LC-MS-condition 01:t _R=0.85 minute; [M+H] ⁺=205.98.

(2-(1,1-two fluoro ethyls) oxazole-4-yl) methyl alcohol:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 2-(1,1-two fluoro ethyls) oxazole-4-carboxylic acid, ethyl ester (1.23 grams; 6.00 the solution in THF (15.0 milliliters) mmole); Under 0 ℃, dropwise be added into lithium aluminium hydride (6.7 milliliters, the 1M solution in THF; 6.70 mmole) in the solution in THF (5.0 milliliters), and reaction mixture stirred 1 hour down in 0 ℃.Add water (2.0 milliliters), then be 1MNaOH (2.0 milliliters) and water (2.0 milliliters), and make reaction mixture be warmed to room temperature.Move down in decompression and to desolventize, and title compound, be water white oil.TLC∶rf(EA)＝0.18。LC-MS-condition 01:t _R=0.57 minute; [M+H] ⁺164.04.

2-(1,1-two fluoro ethyls)-4-((4-nitro-2H-1,2,3-triazole-2-yl) methyl) oxazole:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with (2-(1,1-two fluoro ethyls) oxazole-4-yl) methyl alcohol (505 milligrams, 3.10 mmoles) at anhydrous CH ₂Cl ₂Solution in (15 milliliters) is under 0 ℃, with Et ₃N (0.56 milliliter, 4.03 mmoles) then handles with DMAP (38 milligrams, 0.31 mmole) and Ms-Cl (0.31 milliliter, 3.91 mmoles).After stirring 1.5 hours under 0 ℃, make the reaction cancellation with water.Separate liquid layer, and with water layer with CH ₂Cl ₂(3 *) extraction.Make organic layer with Na ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get 695 milligrams of rough methanesulfonics (2-(1,1-two fluoro ethyls) oxazole-4-yl) methyl esters, be yellow solid.The solution of this crude material in DMF (8 milliliters) is added into through (0.9 milliliter of DIPEA; 5.39 4-nitro-2H-[1 of 30 minutes of pre-treatment mmole); 2,3] triazole (3.08 grams, 10% solution in acetone; 2.70 mmole) in the solution in DMF (10 milliliters), and with reaction mixture in 50 ℃ of following stirred overnight.Add water (30 milliliters), then be EA (50 milliliters).With EA (50 milliliters) extraction, and the organic collection liquid that makes merging is with Na with water layer ₂SO ₄Dehydrate, filter, and under reduced pressure remove solvent.(5: 1 → 2: 1 heptane-EA), obtain title compound are yellow solid: TLC: rf (1: 2 heptane-EA)=0.4 to the purifying of residue through FC.LC-MS-condition 01:t _R=0.89 minute, [M] ⁺=259.11.

2-((2-(1,1-two fluoro ethyls) oxazole-4-yl) methyl)-2H-1,2,3-triazole-4-amine:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 2-(1,1-two fluoro ethyls)-4-((4-nitro-2H-1,2,3-triazole-2-yl) methyl) oxazole (130 milligrams, 0.50 mmole), iron powder (85 milligrams, 1.51 mmoles) and NH ₄The mixture of Cl (136 milligrams, 2.51 mmoles) in the mixture of EtOH (2.0 milliliters) and water (1.0 milliliters) stirred 60 minutes down in 70 ℃.The filtered while hot reaction mixture, and under reduced pressure concentrate.Add CH ₂Cl ₂(10 milliliters) then are 1N NaOH (10 milliliters).With water layer with CH ₂Cl ₂(2 * 10 milliliters) extraction, and the organic collection liquid that makes merging is with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get title compound, be yellow oil.LC-MS-condition 01:t _R=0.66 minute; [M+H] ⁺=230.03.

1-(2-((4-nitro-2H-1,2,3-triazole-2-yl) methyl) thiazole-4-yl) ethyl ketone:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under; With 4-(2-methyl isophthalic acid; 3-dioxolane-2-yl)-(5610 milligrams of 2-((4-nitro-2H-1,2,3-triazole-2-yl) methyl) thiazoles (WO2009077990A1); 18.87 mmole) solution in THF (190 milliliters) is handled with 1N HCl (51.0 milliliters), and with reaction mixture stirred overnight under room temperature.Add 1N NaOH, reaching neutral pH, and product is extracted with EA (2 * 100 milliliters).Organic collection liquid that number merges is with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent.(6: 4 heptane-EA), obtain title compound are yellow solid: TLC: rf (6: 4 heptane-EA)=0.29 to the purifying of residue through FC.LC-MS-condition 02:t _R=0.82 minute.

1-(2-((4-amino-2H-1,2,3-triazole-2-yl) methyl) thiazole-4-yl) ethyl ketone:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 1-(2-((4-nitro-2H-1,2,3-triazole-2-yl) methyl) thiazole-4-yl) ethyl ketone (343 milligrams, 1.35 mmoles), iron powder (229 milligrams, 4.06 mmoles) and NH ₄The mixture of Cl (366 milligrams, 6.77 mmoles) in the mixture of EtOH (6.0 milliliters) and water (3.0 milliliters) stirred 20 minutes down in 85 ℃.The filtered while hot reaction mixture, and under reduced pressure concentrate.Add CH ₂Cl ₂(20 milliliters) then are water (20 milliliters).With water layer with CH ₂Cl ₂(2 * 20 milliliters) extraction, and the organic collection liquid that makes merging is with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get title compound, be yellow oil.LC-MS-condition 02:t _R=0.62 minute; [M+H] ⁺=224.36.

1-(5-((4-amino-2H-1,2,3-triazole-2-yl) methyl) furans-2-yl) ethyl ketone

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with 1-(5-((4-nitro-2H-1,2,3-triazole-2-yl) methyl) furans-2-yl) ethyl ketone (WO2009077990A1) (500 milligrams, 2.12 mmoles), iron powder (358 milligrams, 6.35 mmoles) and NH ₄The mixture of Cl (572 milligrams, 10.59 mmoles) in the mixture of EtOH (8.0 milliliters) and water (4.0 milliliters) stirred 30 minutes down in 85 ℃.The filtered while hot reaction mixture, and under reduced pressure concentrate.Add CH ₂Cl ₂(15 milliliters) then are 1NNaOH (15 milliliters).With water layer with CH ₂Cl ₂(2 * 15 milliliters) extraction, and the organic collection liquid that makes merging is with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get title compound, be yellow oil.LC-MS-condition 02:t _R=0.64 minute; [M+H] ⁺=207.49.

N-(2-((4-(1,1-two fluoro ethyls) oxazole-2-yl) methyl)-2H-1,2,3-triazole-4-yl)-5-(4-iodo-3-aminomethyl phenyl)-2-first base oxazole-4-carboxylic acid amides:

According to general procedure A, from 2-((4-(1,1-two fluoro ethyls) oxazole-2-yl) methyl)-2H-1,2,3-triazole-4-amine and 5-(4-iodo-3-aminomethyl phenyl)-2-first base oxazole-4-carboxylic acid begins.LC-MS-condition 07:tR=1.03 minute; [M+H] ⁺555.03.

N-(2-((4-(1,1-two fluoro ethyls) oxazole-2-yl) methyl)-2H-1,2,3-triazole-4-yl)-5-(4-tritium-3-aminomethyl phenyl)-2-first base oxazole-4-carboxylic acid amides:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame; And under rare gas element (N2); Make N-(2-((4-(1,1-two fluoro ethyls) oxazole-2-yl) methyl)-2H-1,2; 3-triazole-4-yl)-5-(4-iodo-3-aminomethyl phenyl)-2-Jia Ji oxazole-4-carboxylic acid amides (6.0 milligrams, 10.8 micromoles), Et ₃N (3.0 microlitres, 22 micromoles) and Pd (2.35 milligrams, 10%, on charcoal) the suspension-s degassing in DMF (0.6 milliliter) three times, and under 23 ℃, stirred 6 hours down at tritium gas (11Ci).Move down in decompression and to desolventize, and by adding 0.7 milliliter of MeOH exchange destabilization tritium, stirred solution, and under reduced pressure remove solvent.Repeat this method three times.At last, will extract with EtOH (10 milliliters) through the solid of well dried, and make this suspension-s, obtain yellow solution through 0.2 micrometer nylon membrane filtration.The activity of crude product is 261mCi.RCP uses following HPLC system to be measured as 93%:Macherey+Nagel Nucleodur C18 Gravity (5 microns, 4.6 * 150 millimeters); Solvent: A. water, 0.05%TFA; B: acetonitrile, 0.05%TFA; 0-4.5 minute 65%B; 5-9.5 minute 95%B; 10 minutes 65%B; 254 millimicrons; Flow 1.4 ml/min.

Use following HPLC condition, make 74mCi crude product purifying: Macherey+Nagel Nucleodur C18 Gravity (5 microns, 8 * 150 millimeters); Solvent: A: water, 0.1%TFA; B: acetonitrile, 0.1%TFA; 0-5.5 minute 65%B; 6-9.5 minute 95%B; 10 minutes 65%B; 254 millimicrons, flow 4.0 ml/min.

Product is dissolved from part with the water dilution, and add NaHCO ₃, then it is seated on the SPE cartridge case (Phenomenex StrataX, 3 milliliters, 100 milligrams), it with water washing twice, and is dissolved with EtOH (10 milliliters) and to leave.Product shows that radiochemical purity is＞97%, with single-minded activity be the 23Ci/ mmole.

N-(2-((4-acetylthiazole-2-yl) methyl)-2H-1,2,3-triazole-4-yl)-5-(4-iodo-3-aminomethyl phenyl)-2-Jia Ji oxazole-4-carboxylic acid amides:

According to general procedure A, begin from 1-(2-((4-amino-2H-1,2,3-triazole-2-yl) methyl) thiazole-4-yl) ethyl ketone and 5-(4-iodo-3-aminomethyl phenyl)-2-Jia Ji oxazole-4-carboxylic acid.LC-MS-condition 02:tR=1.12 minute; [M+H] +=549.20.

N-(2-((4-acetylthiazole-2-yl) methyl)-2H-1,2,3-triazole-4-yl)-5-(4-tritium-3-aminomethyl phenyl)-2-Jia Ji oxazole-4-carboxylic acid amides:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame; And under rare gas element (N2), make N-(2-((4-acetylthiazole-2-yl) methyl)-2H-1,2; 3-triazole-4-yl)-5-(4-iodo-3-aminomethyl phenyl)-2-Jia Ji oxazole-4-carboxylic acid amides (3.2 milligrams, 5.8 micromoles), Et ₃N (1.6 microlitres, 11.6 micromoles) and Pd (1.55 milligrams, 10%, on charcoal) the suspension-s degassing in EtOH (0.46 milliliter) and dioxy land surround (0.24 milliliter) three times, and under 21 ℃, stirred 5.5 hours down at tritium gas (12Ci).Move down in decompression and to desolventize, by adding 1.0 milliliters of MeOH exchange destabilization tritiums, stirred solution, and under reduced pressure remove solvent.Repeat this method three times.At last, will extract with EtOH (5 milliliters) through the solid of well dried, and make this suspension-s, obtain colourless solution through 0.2 micrometer nylon membrane filtration.The activity of crude product is 111mCi.RCP uses following HPLC system to be measured as 90%:Macherey+NagelNucleodur C8 Gravity (5 microns, 4.6 * 150 millimeters); Solvent: A. water, 0.05%TFA; B: acetonitrile, 0.05%TFA; 0 minute 30%B; 10-14.5 minute 95%B; 15 minutes 30%B; 290 millimicrons; Flow 1.0 ml/min.

Use following HPCL condition, make 60mCi crude product purifying: Macherey+Nagel Nucleodur C18 Gravity (5 microns, 8 * 150 millimeters); Solvent: A: water, 0.1%TFA; B: acetonitrile, 0.1%TFA; 53%B; 254 millimicrons, flow 3.1 ml/min.

Product is dissolved from part concentrate, add NaHCO ₃, then it is seated on the SPE cartridge case (Phenomenex StrataX, 3 milliliters, 100 milligrams), it with water washing twice, and is dissolved with EtOH and to leave.Product shows that radiochemical purity is＞98%, with single-minded activity be the 19Ci/ mmole.

N-(2-((5-acetyl furan-2-yl) methyl)-2H-1,2,3-triazole-4-yl)-5-(4-iodo-3-aminomethyl phenyl)-2-Jia Ji oxazole-4-carboxylic acid amides:

According to general procedure A, begin from 1-(5-((4-amino-2H-1,2,3-triazole-2-yl) methyl) furans-2-yl) ethyl ketone and 5-(4-iodo-3-aminomethyl phenyl)-2-Jia Ji oxazole-4-carboxylic acid.LC-MS-condition 02:t _R=1.12 minutes; [M+H] ⁺=549.20.

N-(2-((5-acetyl furan-2-yl) methyl)-2H-1,2,3-triazole-4-yl)-5-(4-tritium-3-aminomethyl phenyl)-2-Jia Ji oxazole-4-carboxylic acid amides:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and under rare gas element (N2), make N-(2-((5-acetyl furan-2-yl) methyl)-2H-1; 2,3-triazole-4-yl)-(10 milligrams of 5-(4-iodo-3-aminomethyl phenyl)-2-Jia Ji oxazole-4-carboxylic acid amides (3.0 milligrams, 5.6 micromoles), DIPEA (0.05 milliliter) and Pd; 10%; On charcoal) the suspension-s degassing in EtOH (3.0 milliliters) and DMF (1.0 milliliters) three times, and under room temperature, stirred 2.0 hours down at tritium gas (5Ci).Remove catalyzer through filtration, and remove the destabilization tritium to drying up from EtOH by repeated evaporation.Use following HPCL condition purifying: Hypersil BDS C18 (5 microns, 4.6 * 250 millimeters); Solvent: A: water, 0.1%TFA; B: acetonitrile, 0.1%TFA; Gradient liquid 100%A → 100%B went through 30 minutes, flow 1.0 ml/min.

3-(the dimethylamino)-fluorine-based oil of Niobe of 4-:

In be equipped with magnetic stirring bar in the dry round-bottomed flask of flame, and at rare gas element (N ₂) under, with the fluorine-based oil of Niobe of 3-amino-4-(1.55 grams, 9.16 mmoles), polyoxymethylene (8.25 grams, 91.63 mmoles) and NaBH ₃The mixture of CN (1.73 grams, 27.49 mmoles) is handled with acetic acid (90 milliliters), and formed mixture was stirred under room temperature 4 hours.With saturated Na ₂CO ₃The aqueous solution is added in the reaction mixture, and the pH value is adjusted to 7-8.With mixture with CH ₂Cl ₂(3 * 55 milliliters) extraction, and the organic collection liquid that makes merging is with MgSO ₄Dehydrate, filter, and under reduced pressure remove solvent, and get title compound, be orange oil.LC-MS-condition 05c uses Waters Atlantis T3, and 5 microns, 4.6 * 30 millimeters tubing string: t _R=0.76 minute; [M+H] ⁺=198.38.

Between 2-methyl-5--tolyl-oxazoles-4-carboxylic acid:

One after the other according to general procedure F, G and E, between 3-ketone group-3--tolyl-ethyl propionate begins and processes.LC-MS-condition 02:t _R=0.85 minute; [M+H] ⁺=218.46.

5-(3-chloro-phenyl-)-2-methyl-oxazoles-4-carboxylic acid:

One after the other according to general procedure K, F, G and E, begin and process from 3-chloro-phenylformic acid.LC-MS-condition 02:t _R=0.87 minute; [M+H] ⁺=238.06.

2-methyl-5-phenyl-oxazoles-4-carboxylic acid:

One after the other according to general procedure F, G and E, begin and process from 3-ketone group-3-phenyl-ethyl propionate.LC-MS-condition 02:t _R=0.76 minute; [M+H] ⁺=204.03.

2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-carboxylic acid:

One after the other, process from beginning 3-trifluoromethyl-phenylformic acid according to general procedure K, F, G and E.LC-MS-condition 02:t _R=0.91 minute; [M+H] ⁺=272.05.

2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-carboxylic acid:

One after the other according to general procedure K, F, G and E, begin and process from 3-trifluoromethoxy-phenylformic acid.LC-MS-condition 02:t _R=0.93 minute; [M+H] ⁺=288.06.

5-(4-fluorophenyl)-oxazoles-4-carboxylic acid:

One after the other according to general procedure K, J, I, H and E, begin and process from 4-fluoro-phenylformic acid.LC-MS-condition 02:t _R=0.80 minute; [M+AcCN+H] ⁺=249.04.

Between 5--tolyl-oxazoles-4-carboxylic acid:

One after the other according to general procedure J, I, H and E, between 3-ketone group-3--tolyl-ethyl propionate begins and processes.LC-MS-condition 02:t _R=0.83 minute; [M+H] ⁺=204.17.

5-(3-methoxyl group-phenyl)-oxazoles-4-carboxylic acid:

One after the other according to general procedure J, I, H and E, begin and process from 3-(3-methoxyl group-phenyl)-3-ketone group-ethyl propionate.LC-MS-condition 02:t _R=0.80 minute; [M+H] ⁺=220.13.

2-ethyl-5-phenyl-oxazoles-4-carboxylic acid:

One after the other according to general procedure J, I, H and E, begin and process from 3-ketone group-3-phenyl-ethyl propionate.LC-MS-condition 02:t _R=0.85 minute; [M+H] ⁺=218.19.

2-cyclopropyl-5-phenyl-oxazoles-4-carboxylic acid:

One after the other according to general procedure J, I, H and E, begin and process from 3-ketone group-3-phenyl-ethyl propionate.LC-MS-condition 02:t _R=0.87 minute; [M+H] ⁺=230.17.

5-(3-fluorophenyl)-oxazoles-4-carboxylic acid:

One after the other according to general procedure K, J, I, H and E, begin and process from 3-fluoro-phenylformic acid.LC-MS-condition 02:t _R=0.80 minute; [M+AcCN+H] ⁺=249.09.

5-(3-chloro-phenyl-)-oxazoles-4-carboxylic acid:

One after the other according to general procedure K, J, I, H and E, begin and process from 3-chloro-phenylformic acid.LC-MS-condition 02:t _R=0.85 minute; [M+AcCN+H] ⁺=265.23.

5-(3-dimethylamino-phenyl)-oxazoles-4-carboxylic acid:

One after the other according to general procedure M and E, begin and process from 3-dimethylamino-phenylformic acid.LC-MS-condition 02:t _R=0.60 minute; [M+H] ⁺=233.36.

5-(3-fluorine-based-5-methyl-phenyl)-2-methyl-oxazoles-4-carboxylic acid:

One after the other according to general procedure N, O, P and E, from 3-fluorine-based-the 5-tolyl acid begins and processes.LC-MS-condition 02:t _R=0.88 minute; [M+H] ⁺=277.28.

5-(3,5-two fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid:

One after the other according to general procedure N, O, P and E, from 3,5-two fluoro-phenylformic acid begin and process.LC-MS-condition 02:t _R=0.86 minute; [M+AcCN+H] ⁺=281.19.

5-(4-iodo-3-aminomethyl phenyl)-2-Jia Ji oxazole-4-carboxylic acid:

One after the other according to general procedure K, Q, G and E, begin and process from 4-iodo-3-tolyl acid.LC-MS-condition 02:t _R=0.94 minute; [M+H] ⁺=344.24.

5-(3-(dimethylamino)-4-fluorophenyl) oxazole-4-carboxylic acid:

One after the other according to general procedure E, M and E, begin and process from 3-(dimethylamino)-fluorine-based oil of Niobe of 4-.LC-MS-condition 02:t _R=0.94 minute; [M+H] ⁺=344.24.

5-(3-(dimethylamino)-4-fluorophenyl)-2-Jia Ji oxazole-4-carboxylic acid:

One after the other according to general procedure E, M, O, H, E, begin and process from 3-(dimethylamino)-fluorine-based oil of Niobe of 4-.LC-MS-condition 05c uses Waters AtlantisT3, and 5 microns, 4.6 * 30 millimeters tubing string: t _R=0.59 minute; [M+H] ⁺=265.25.

The preparation of embodiment

Embodiment 1:

Between 2-methyl-5--tolyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure A, between 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5--tolyl-oxazole-4-carboxylic acid begins.

LC-MS-condition 02:t _R=1.12 minutes; [M+H] ⁺=427.83.

Embodiment 2:

5-phenyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure A, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazole-4-carboxylic acid.

LC-MS-condition 01:t _R=1.01 minutes; [M+H] ⁺=416.90.

Embodiment 3:

Between 2-methyl-5--tolyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure A, between 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5--tolyl-oxazole-4-carboxylic acid begins.

LC-MS-condition 02:t _R=1.10 minutes; [M+H] ⁺=445.09.

Embodiment 4:

2-methyl-5-phenyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.08 minutes; [M+H] ⁺=413.79.

Embodiment 5:

5-(3,5-two fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3,5-two fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.62 minutes; [M+H] ⁺=466.70.

Embodiment 6:

2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.68 minutes; [M+H] ⁺=498.74.

Embodiment 7:

5-(3-chloro-phenyl-)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-chloro-phenyl-)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.58 minutes; [M+H] ⁺=433.72.

Embodiment 8:

5-(3-methoxyl group-phenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-methoxyl group-phenyl)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.40 minutes; [M+H] ⁺=446.75.

Embodiment 9:

2-cyclopropyl-5-phenyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 2-cyclopropyl-5-phenyl-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.68 minutes; [M+H] ⁺=456.74.

Embodiment 10:

2-methyl-5-phenyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.49 minutes; [M+H] ⁺=430.72.

Embodiment 11:

5-(3-fluorophenyl)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-fluorophenyl)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.48 minutes; [M+H] ⁺=417.76.

Embodiment 12:

5-(3-chloro-phenyl-)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-chloro-phenyl-)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.53 minutes; [M+H] ⁺=450.67.

Embodiment 13:

5-(3-fluorine-based-5-methyl-phenyl)-2-methyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-fluorine-based-5-methyl-phenyl)-2-methyl-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.65 minutes; [M+H] ⁺=462.74.

Embodiment 14:

2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.72 minutes; [M+H] ⁺=514.74.

Embodiment 15:

5-(3-chloro-phenyl-)-2-methyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-chloro-phenyl-)-2-methyl-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.70 minutes; [M+H] ⁺=447.75.

Embodiment 16:

5-(4-fluorophenyl)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(4-fluorophenyl)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.47 minutes; [M+H] ⁺=417.76.

Embodiment 17:

Between 5--tolyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, between 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5--tolyl-oxazole-4-carboxylic acid begins.

LC-MS-condition 06:t _R=1.49 minutes; [M+H] ⁺=430.73.

Embodiment 18:

5-(3,5-two fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3,5-two fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.66 minutes; [M+H] ⁺=449.74.

Embodiment 19:

5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.55 minutes; [M+H] ⁺=442.5.

Embodiment 20:

5-(3-fluorophenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-fluorophenyl)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.42 minutes; [M+H] ⁺=434.74.

Embodiment 21:

5-(3-methoxyl group-phenyl)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-methoxyl group-phenyl)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.46 minutes; [M+H] ⁺=429.79.

Embodiment 22:

5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.50 minutes; [M+H] ⁺=459.89.

Embodiment 23:

Between 5--tolyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, between 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5--tolyl-oxazole-4-carboxylic acid begins.

LC-MS-condition 06:t _R=1.54 minutes; [M+H] ⁺=413.79.

Embodiment 24:

2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.72 minutes; [M+H] ⁺=481.8.

Embodiment 25:

5-(4-fluorophenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(4-fluorophenyl)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.42 minutes; [M+H] ⁺=434.74.

Embodiment 26:

5-(3-fluorine-based-5-methyl-phenyl)-2-methyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-fluorine-based-5-methyl-phenyl)-2-methyl-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.70 minutes; [M+H] ⁺=445.79.

Embodiment 27:

2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.76 minutes; [M+H] ⁺=497.74.

Embodiment 28:

5-phenyl-oxazole-4-carboxylic acid { 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[5-(1,1-two fluoro-ethyls)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.49 minutes; [M+H] ⁺=399.78.

Embodiment 29:

5-(3-chloro-phenyl-)-2-methyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-chloro-phenyl-)-2-methyl-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.71 minutes; [M+H] ⁺=464.70.

Embodiment 30:

2-ethyl-5-phenyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure Z2, begin from 2-[4-(1,1-two fluoro-ethyls)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 2-ethyl-5-phenyl-oxazole-4-carboxylic acid.

LC-MS-condition 06:t _R=1.69 minutes; [M+H] ⁺=444.72.

Embodiment 31:

Between 2-methyl-5--tolyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure A, between 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5--tolyl-oxazole-4-carboxylic acid begins.

LC-MS-condition 01:t _R=1.05 minutes; [M+H] ⁺=429.06.

Embodiment 32:

N-(2-((2-(1,1-two fluoro ethyls) oxazole-4-yl) methyl)-2H-1,2,3-triazole-4-yl)-2-methyl-5-(-tolyl) oxazole-4-carboxylic acid amides:

According to general procedure A, from 2-((2-(1,1-two fluoro ethyls) oxazole-4-yl) methyl)-2H-1,2, between 3-triazole-4-amine and 2-methyl-5--tolyl-oxazole-4-carboxylic acid begins.

LC-MS-condition 01:t _R=1.05 minutes; [M+H] ⁺=429.06.

Embodiment 33:

2-methyl-5-phenyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure A, begin from 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-benzene base oxazole-4-carboxylic acid.

LC-MS-condition 08:t _R=1.28 minutes; [M+H] ⁺=415.00.

Embodiment 34:

5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure A, begin from 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-(dimethylamino) phenyl) oxazole-4-carboxylic acid.

LC-MS-condition 08:t _R=1.29 minutes; [M+H] ⁺=444.04.

Embodiment 35:

5-(3-dimethylamino-4-fluorophenyl)-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure A, begin from 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-(dimethylamino)-4-fluorophenyl) oxazole-4-carboxylic acid.

LC-MS-condition 05c uses Waters Atlantis T3, and 5 microns, 4.6 * 30 millimeters tubing string: t _R=0.91 minute; [M+H] ⁺=462.14.

Embodiment 36:

5-(3-dimethylamino-4-fluorophenyl)-2-methyl-oxazole-4-carboxylic acid { 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:

According to general procedure A, begin from 2-[4-(1,1-two fluoro-ethyls)-oxazole-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-(dimethylamino)-4-fluorophenyl)-2-first base oxazole-4-carboxylic acid.

LC-MS-condition 05c uses Waters Atlantis T3, and 5 microns, 4.6 * 30 millimeters tubing string: t _R=0.95 minute; [M+H] ⁺=476.18.

II. Biological Detection

In vitro detect

The ALX acceptor of formula (I) compound urges the agent activity according to following determination of experimental method.

Experimental technique:

Cellular calcium tolerance:

Making the cell that shows recombinant human ALX acceptor and G-protein G α 16 (HEK293-hALXR-G α 16) in growth medium (GM), grow to 80% converges.(Invitrogen 13151-014) makes the cell detachment petridish, and under room temperature with the cell dissociation buffer reagent; 1; Under the 000rpm,, be collected in and detect damping fluid (the AB) (HankShi BSS (Gibco that equates appearance part by centrifugal 5 minutes; 14065-049) with do not have among the phenol red DMEM (Gibco, 11880-028)).Under 37 ℃, at 5%CO ₂Down, in (Invitrogen, F14202) (Gibco, after the cultivation in 60 minutes, with cell washing, and resuspending is in AB among AB 15630-056) with 20mM HEPES through replenishing 1 μ M Fluo-4 (AM).Then, it under 50,000 cells, with every well 70 microlitres, is seeded on the 384-well FLIPR check-out console (Greiner, 781091), and by 1 under the 000rpm centrifugal 1 minute and by sedimentation.The stock solution of testing compound constitutes in DMSO under the concentration of 10mM, and in AB, is diluted to continuity the needed concentration of activation dose response curve.WKYMVm (Phoenix polypeptide) urges agent as a reference and uses.FLIPR Tetra instrument (molecular device company) adds 4 microlitres and under 10mM, has been dissolved in the testing compound among the DMSO according to mfr's standard specification operation, and in detecting damping fluid, diluting before the experiment, to obtain desired final concn.Change on the fluorescence is under lex=488 millimicron and lem=540 millimicron, with monitoring afterwards before adding testing compound.The emission peak that is higher than basic content after compound adds is exported behind baseline deduction.Numerical value is carried out normalization to the high-content control group (WKYMVm compound, 10nM final concn) behind baseline value (AB interpolation) deduction.

Urge agent activity (EC about the ALX acceptor of compound for example ₅₀Value) is shown in the table 1.

Table 1

About using human liver microsomes, at reactive metabolism product and protein Between its valency bonded detect

The purpose that said covalent attachment detects is for measuring after there is cultivation down in the NADPH regeneration system rapidly, per hour in the reactive metabolism product of human liver microsome (HLM) and the covalent attachment amount between protein.Measured covalent attachment speed is with pmol bound drug equivalent/milligram protein/hour expression.If compound has with covalent manner and is bonded to proteinic low propensity, then it is known advantage.

Cultivate

Will through radioactivity mark's compound ( ³H or ¹⁴C) under the concentration of 10 μ M, in 0.1M phosphate buffer (pH 7.4), in having the MC single 96 well plates of 1.0 mg/ml human livers, cultivate.For reaching this purpose, it is 250 microlitres that the 1mM stock solution that is added on volume made in indivedual solvents (ethanol) and is 2.5 microlitres reaches last volume.(20IU/ milliliter desaturase, 25 microlitres have 11mM NADP sodium salt, 100mM G-6-P disodium salt, the 100mMMgCl in 0.1M Tutofusin tris (Tris) damping fluid to be incubated at the NADPH-regeneration system rapidly with glucose-6-phosphate dehydrogenase (G6PD) ₂, pH 7.4) do not exist or exist down, and under not the existing or exist of 5mM GSH, carry out in addition, with capture reaction property intermediate.The initial blank value of also record no NADPH, not cultivating is to measure non-single-minded quick combination.Be reflected at the multiscreen deep-well solvinert 96 hydrophobicity PTFE filter plate (Millipore that contain the ice-cold acetonitrile of 260 microlitres; Zug, Switzerland) on, initial by adding 25 microlitre NADPH-regeneration system rapidlys; And after one hour, stop by adding 200 microlitre culturing mixt.The precipitating action of microsomal protein matter under 600rpm, is accomplished via making plate vibration 15 minutes under 15 ℃ temperature.At last, settled culture in electricrefrigerator, is stored 15 minutes down at 4 ℃.

Protein with filtrate under 10 ℃, 1800 the gram under separated by centrifugal 20 minutes.By down centrifugal of 1500 grams, 10 ℃ and 2 minutes, the protein pill is washed with 800 microliter methanol/0.1% sulfuric acid (v/v), to remove non-single-minded combination.The repeated washing step 6 is inferior.The protein pill that has washed is dissolving again by adding 500 microlitre 0.1% (w/v) NaOH/1% (w/v) the SDS aqueous solution.Make filter plate under 60 ℃, vibration is 45 minutes under 400rpm, and under 35 ℃, and under 2000 grams centrifugal 20 minutes.Repeat this step once, and merge protein soln.

Mensuration about total radioactivity; Be 400 microlitre protein solns and 4 milliliters of liquid flicker soup (Irga Safe plus with a liquid part; Perkin Elmer, Z ü rich Switzerland) mixes; And use Tricarb2300TR liquid scintillation analyzer (Perkin Elmer) with luminous correction and online quench correction, by outer standard substance ( ¹³³Ba) analyze.About the mensuration of total protein content, the 20 microlitre protein solns of a liquid part use BCA protein detection external member, and (Perbio Science Switzerland SA, Lausanne Switzerland) analyze.The amount that is covalently bond to microsomal protein matter is calculated as described below: the normal amount of measured bound drug (deducting the normal amount background of institute's bound drug) that will have a NADPH with NADPH divided by in each well through dissolving the proteinic amount of calculating of washed protein pill again; Obtain the normal amount of bound drug, represent with pmol/milligram protein per hour.

Compare with the embodiment 18 and 75 of WO 2009/077990, following result confirms the superior covalent attachment effect form of the application's case embodiment 31, and this shows the low danger about adverse side effect; Preparation through the compound of tritiate is described in the experiment partly.

Claims

1. a formula (I) compound,

Wherein

R ¹The expression phenyl, it is without replacement, replaces through single replacement or two, and wherein substituting group independently is selected from the cohort of following composition: halogen, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy and dimethylamino; And

R ²Expression hydrogen, methyl, ethyl or cyclopropyl;

Or the salt of this kind compound.

2. formula according to claim 1 (I) compound, wherein

A representes to be selected from the group of furyl 、 oxazolyl and thiazolyl, and wherein two of this group tie points are 1, and 3-arranges;

R ¹The expression phenyl, it be without replacing, replace or two replacements through single, wherein substituting group independently is selected from the cohort of following composition: fluorine-based, chloro, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy and dimethylamino; And

R ²Expression hydrogen, methyl or ethyl;

Or the salt of this kind compound.

3. according to each described formula (I) compound in claim 1 or 2, wherein

A representes furans-2,5-two Ji 、 oxazoles-2,4-two bases or thiazole-2,4-two bases;

Or the salt of this kind compound.

4. according to each described formula (I) compound in claim 1 or 3, wherein

A representes furans-2,5-two bases;

Or the salt of this kind compound.

5. according to each described formula (I) compound in claim 1 or 3, wherein

A Biao Shi oxazole-2,4-two bases;

Or the salt of this kind compound.

6. according to each described formula (I) compound in claim 1 or 3, wherein

A representes thiazole-2,4-two bases;

Or the salt of this kind compound.

7. according to each described formula (I) compound in claim 1 or 6, wherein

R ¹Expression is without substituted phenyl;

Or the salt of this kind compound.

8. according to each described formula (I) compound in claim 1 or 6, wherein

R ¹The expression phenyl, it is replaced by fluorine-based, chloro, methyl or trifluoromethyl list;

Or the salt of this kind compound.

9. according to each described formula (I) compound in claim 1 or 8, wherein

R ²Expression hydrogen;

Or the salt of this kind compound.

10. according to each described formula (I) compound in claim 1 or 8, wherein

R ²Expression methyl or ethyl;

Or the salt of this kind compound.

11. formula according to claim 1 (I) compound, it is selected from the cohort of following composition:

Or the salt of this kind compound.

12. formula according to claim 1 (I) compound, it is selected from the cohort of following composition:

Or the salt of this kind compound.

13. formula according to claim 1 (I) compound or its pharmacy acceptable salt, it is as medicament.

14. a medical composition, it contains formula according to claim 1 (I) compound or its pharmacy acceptable salt as active ingredient, and inert excipient at least a treatment.

15. formula according to claim 1 (I) compound or its pharmacy acceptable salt purposes on medicament is made; This medicament is used for prevention or treatment disease, is selected from inflammatory diseases, obstructing airway disease, ThermoScript II virus infection, cardiovascular disorder, neural inflammation, nervous disorders, pain, the disease that Protein virus mediated and the illness that amyloid mediated that allergic conditions, HIV mediated; And be used to regulate immunne response.

16. formula according to claim 1 (I) compound or its pharmacy acceptable salt; It is used for prevention or treatment disease, is selected from inflammatory diseases, obstructing airway disease, ThermoScript II virus infection, cardiovascular disorder, neural inflammation, nervous disorders, pain, the disease that Protein virus mediated and the illness that amyloid mediated that allergic conditions, HIV mediated; And be used to regulate immunne response.